KR20160067985A - Heterocyclic modulators of ATP-binding cassette transporters - Google Patents

Abstract

The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful as modulators of ATP-linked cassette ("ABC") transporters or fragments thereof, including cystic fibrosis transverse membrane conduction regulators ("CFTR"). The present invention also relates to a method of treating ABC transporter mediated diseases using the compounds of the present invention.

Description

Heterocyclic modulators of ATP-binding cassette transporters < RTI ID = 0.0 >

The present invention relates to a modulator of an ATP-linked cassette ("ABC") transporter or fragment thereof, including a cystic fibrosis transverse membrane conduction regulator ("CFTR"), compositions thereof and methods of using the same. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

ABC transporters are a class of membrane transporter proteins that regulate the transport of anions, as well as a wide variety of pharmacological agents, potentially toxic drugs and bio-organisms. ABC transporter is a homogeneous membrane protein that binds and uses adenosine triphosphate (ATP) of the cell for its specific activity. Some of these transporters have been found to be multidrug resistant proteins (such as MDR1-P glycoproteins or multidrug resistance proteins, such as MRP1) that defend against malignant cancer cells against chemotherapeutic agents. Up to now, 48 ABC transporters have been identified and grouped into seven classes based on their sequence identification and function.

ABC transporters regulate diverse and important physiological roles in the body and provide protection against harmful environmental compounds. Because of this, it represents an important potential drug target for the treatment of diseases associated with transporter defects, the prevention of drug delivery outside the target cell, and the mediation of other diseases for which adjustment of ABC transporter activity may be beneficial.

One member of the ABC transporter class generally associated with disease is the cAMP / ATP mediated anion channel, CFTR. CFTR is expressed in a variety of cell types, including absorptive and secretory epithelial cells, which control the activity of other ion channels and proteins as well as anionic flux across the membrane. In epithelial cells, the normal function of CFTR is important in maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR consists of about 1480 amino acids that encode a protein consisting of a series of repeats of the transverse membrane domain, each containing six transverse membrane spirals and a nucleotide binding domain. The two trans-membrane domains are connected by a large, polar regulatory (R) -domain with multiple phosphorylation sites that regulate channel activity and cell-traking.

The gene encoding CFTR has been identified and sequenced (Gregory, R. J. et al. (1990) Nature 347: 382-386; Rich, D. P. et al. (1990) Nature 347: 358-362). (Riordan, JR et al. (1989) Science 245: 1066-1073] Mutations in CFTR due to genetic defects lead to cystic fibrosis, the most common fatal genetic disease in humans CF "). Cystic fibrosis occurs in about 1 out of every 2,500 babies in the US In the United States, less than 10 million people have a single copy of the defective gene without apparent adverse effects In contrast, CF Individuals with two copies of the gene of interest are suffering from a fatal weakening of CF, including chronic lung disease.

In patients with cystic fibrosis, internally expressed CFTR mutations in the respiratory epithelium lead to reduced apical anion secretion, resulting in an imbalance of ion and fluid transport. The resulting reduction in anion transport, together with enhanced mucus accumulation in the lung, causes microbial infection and ultimately leads to death of CF patients. Besides respiratory diseases, CF patients usually suffer from gastrointestinal problems and impaired function, leading to death if not treated. In addition, the vast majority of males with cystic fibrosis are infertile and their reproductive capacity decreases between females with cystic fibrosis. In contrast to the severe effects of two copies of the CF-related gene, individuals with a single copy of the CF-associated gene exhibit increased resistance to dehydration due to cholera and diarrhea, accounting for the relatively high frequency of CF genes in the population do.

Sequence analysis of the CFTR gene of the CF chromosome revealed various disease inducing mutations (see Cutting, GR et al. (1990) Nature 346: 366-369; Dean, M. et al. Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87: 8447-8451). So far, disease-causing mutations of more than 1000 CF genes have been identified (http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as ΔF508-CFTR. These mutations occur in about 70% of the causes of cystic fibrosis and are associated with serious disease.

Deletion of residue 508 of ΔF508-CFTR prevents the initial protein from folding properly. This makes the mutant protein unable to enter the ER and causes trafficking in the plasma membrane. As a result, the number of channels present in the membrane is much less than that observed in cells expressing the wild-type CFTR. In addition to corrupted traffic kings, mutations cause fault channel gating. In addition, a reduced number of channels of membrane and defect gating leads to reduced anion transport across the epithelium leading to defect ions and fluid transport (see Quinton, PM (1990), FASEB J. 4: 2709- 2727). However, through research, it has been found that the reduced number of membranes? F508-CFTR is less than wild type CFTR but functional (Dalemans et al. (1991) Nature Lond. 354: 526-528; Denning et al. , supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to [Delta] F508-CFTR, other disease-causing mutations of CFTR that cause defective traffic-killing, synthesis and / or channel gating may be upregulated or downregulated to alter anion secretion and alter disease progression and / or severity.

Although CFTR transports a variety of molecules in addition to anions, this role (anion transport) represents an important component of the transport of ions and water across the epithelium. Other elements include epithelial Na ⁺ channels, ENaC, Na ⁺ / 2Cl ^- / K ⁺ airtransplants, Na ⁺ -K ⁺ -ATPase pumps, and basolateral membrane K ⁺ channels, which serve to uptake chloride into cells .

These elements together act to achieve direct transport across the epithelium, through selective expression thereof and their location in the cell. Chloride uptake is caused by the cooperative activity of ENaC and CFTR present on the top membrane and the Na ⁺ -K ⁺ -ATPase pump and Cl-channel expressed on the basolateral surface of the cell. The second active transport of chloride from the caliber side induces the accumulation of intracellular chloride, which in turn causes the vector to passively pass through the Cl ^- channel. Arrangements of Na ⁺ / 2Cl ^- / K ⁺ airway transfusions, Na ⁺ -K ⁺ -ATPase pumps and basolateral membrane K ⁺ channels on the basolateral side surface and CFTR on the aperture side cooperate with the secretion of chloride through the CFTR on the caliber side . Since water is generally not actively self-transported, its flow across the epithelium depends on the small epithelial osmotic gradient generated by the bulk flow of sodium and chloride.

In addition to cystic fibrosis, modulation of CFTR activity may be beneficial in other diseases not directly caused by mutations in CFTR, such as secretory diseases mediated by CFTR and other protein folding diseases. These diseases include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome.

COPD is characterized by progressive or non-reversible airflow limitations. The airflow limit is due to mucus hypersecretion, air species and bronchiolitis. Activators of mutant or wild-type CFTR provide a potential treatment for mucus hypersecretion and damaged mucociliary clearance common to COPD. Specifically, increased anion secretion across the CFTR facilitates fluid transport to the airway surface liquid, which can hydrate the mucus and optimized ciliate ambient viscosity. This will lead to enhanced mucociliary clearance and reduced symptoms associated with COPD. Dry eye disease is characterized by decreased tear production and abnormal tear film lipid, protein and mucin profiles. There are a number of causes of ocular dryness, some of which include age, LASIK, arthritis, medication, chemical / thermal burns, allergies and diseases such as cystic fibrosis and Sulleren syndrome. Increased anion secretion via CFTR will enhance fluid transport from the corneal epithelial cells and glands surrounding the eye to increase corneal hydration. This will help alleviate the symptoms associated with eye dryness. Sjörenren's syndrome is an autoimmune disease in which the immune system attacks the moisture-producing line through the body, including the eyes, mouth, skin, respiratory tract, liver, vagina, and intestines. Symptoms include dry eye, mouth and vaginal as well as pulmonary disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis and multiple myositis / dermatomyositis. Defective protein traffic is thought to cause disease, which limits treatment options. A modulator of CFTR activity may help hydrate the various organs suffered by the disease and elevate the associated symptoms.

As discussed above, the deletion of 508 residues of ΔF508-CFTR is believed to prevent the early proteins from folding properly, thereby causing these mutant proteins to enter the ER and to cause traffic to the plasma membrane. As a result, an insufficient amount of mature protein is present in the plasma membrane, and the transport of chloride in epithelial tissue is markedly reduced. In fact, this intracellular phenomenon of defective ER treatment of ABC transporters by ER machines has been found to be a fundamental basis for CF disease as well as for a wide range of other isolated genetic disorders. Two methods by which the ER machinery can become impaired are to induce degradation by loss of coupling to the ER propagation of the protein or to accumulate the ER of such defective / malfunctioning protein (Aridor M, et al ., Nature Med., 5 (7), pp 745-751 (1999); Shastry, BS, et al ., Neurochem. International, 43 , pp 1-7 (2003); Rutishauser, J., et al ., Swiss Med Wkly, 132 , pp 211-222 (2002); Morello, JP et al ., TIPS, 21 , pp. 466-469 (2000); Bross P., et al ., < / RTI > Human Mut., 14 , pp. 186-198 (1999)). Diseases associated with the first class of ER dysfunction are cystic fibrosis (due to the misfolded < RTI ID = 0.0 > [Delta] F508-CFTR as discussed above), hereditary emphysema (due to a1- antitrypsin, not Piz variant), hereditary hemochromatosis, Dyslipidemia, such as protein C deficiency, type 1 hereditary vascular edema, lipid deficiency disorders, such as familial hypercholesterolemia, type 1 kelmicronemia, unbeta lipoproteinemia, lysosomal storage disease, (Due to lysosomal processing enzymes), Sandhof / Tay-Sachs (due to β-hexosaminidase), Type II (Due to UDP-glucuronyl-sialic-transferase), hyperglycaemic disorders / hyperinsulinemia, diabetes (due to insulin receptors), dwarfism (due to growth hormone receptors) , Myeloperoxidase deficiency, primary parathyroid gland Hyperplasia (due to preproparathyroid hormone), melanoma (due to tyrosinase). Diseases related to the latter class of ER dysfunction include type 1 glycan degradation CDG, hereditary emphysema (due to α1 antitrypsin (due to the Piz variant), congenital hyperthyroidism, incomplete osteogenesis (I, II, IV pro Collagen), hereditary hypofibrinogenesis (due to fibrinogen), ACT deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neuroblastoma diabetes insipidus (due to vasopressin hormone / V2- , Neurodegenerative diseases such as Alzheimer ' s disease (beta APP < RTI ID = 0.0 > And presenilin), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neuropathy such as Huntington's disease, type I spinal cord cerebellar ataxia, vertebral and bulbar muscular dystrophy, The enemy (Due to prion protein processing deficiencies), Fabry disease (due to lysosomal a-galactosidase A), as well as spongiform encephalopathy, such as hereditary Crohn ' s disease, And Strasler-Shinkler syndrome (due to Prp processing defects).

In addition to upregulation of CFTR activity, reducing anion secretion by CFTR modulators may be advantageous in the treatment of secretory diarrhea, where epithelial water transport is greatly increased due to secretory-promoted water-activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR.

Although there are many causes of diarrhea, the main consequences of diarrheal disease caused by excessive chloride transport are common to all and include dehydration, acidosis, impaired growth and death.

Acute and chronic diarrhea represent a major medical problem in many parts of the world. Diarrhea is an important cause of malnutrition and is the leading cause of death in infants under 5 years (5,000,000 deaths a year).

Secretory diarrhea is also a risk for acquired immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD) patients. From industrialized countries to developing countries, diarrhea accounts for 16 million travelers each year, and the severity of diarrhea and the number of cases vary according to travel destination and region.

Cattle, pets, horses, sheep, goats, cats and dogs, also known as scorers, are also major causes of death in these animals. Diarrhea can occur from any major metastasis, such as a cause and physical movement, as well as a response to various bacterial or viral infections, and generally occurs within the first few hours of an animal's life.

The most common diarrhea-causing bacteria are enterotoxogenic E-coli (ETEC) with a K99 pillus antigen. Common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents include, among others, cryptosporidium, giardia lamblia and salmonella.

Symptoms of rotavirus infection include water, dehydration and weakness. Coronaviruses cause more serious disease in newborn animals and have a higher mortality rate than rotavirus infections. However, often young animals can be infected with more than one virus or virus and a combination of bacterial microorganisms at a time. This greatly increases the severity of the disease.

Accordingly, there is a need for a modulator of ABC transporter activity and compositions thereof that can be used to modulate the activity of ABC transporters in mammalian cell membranes.

Methods of treating ABC transporter mediated diseases using such modulators of ABC transporter activity are desired.

Methods of modulating ABC transporter activity in mammalian in vitro cell membranes are required.

There is a need for modulators of CFTR activity that can be used to modulate the activity of CFTR in mammalian cell membranes.

Methods of treating CFTR mediated diseases using such modulators of CFTR activity are desired.

Methods are needed to modulate CFTR activity in mammalian in vitro cell membranes.

In accordance with the present invention, the compounds of the present invention and pharmaceutically acceptable compositions thereof have been found to be useful as modulators of ABC transporter activity. Said compound being a compound of formula I or a pharmaceutically acceptable salt thereof.

Formula I

In the above formula (I)

R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ and n are as defined herein.

Such compounds and pharmaceutically acceptable compositions include, but are not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency, such as protein C deficiency, type 1 hereditary vascular edema, lipid treatment Deficiency, such as, for example, familial hypercholesterolemia, type 1-chylomicronemia, non-beta lipoproteinemia, lysosomal storage diseases such as I-cell disease / hypoglycemia, mucopolysaccharidosis, Diabetes mellitus, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type 1 glycan degradation CDG, hereditary emphysema, congenital hypomagnesemia, congenital hypothyroidism, (DI), neuroblastoma diabetes insipidus, idiopathic diabetes insipidus, Charcot-Maritou syndrome, Periza euus-mer, < RTI ID = 0.0 & Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's disease, type I spinal cord cerebellar ataxia, vertebrae And hereditary cerebral infarction as well as atrophic encephalopathy such as hereditary Crohn's disease, Fabry's disease, Strasler-Shinkler syndrome, COPD, dry eye syndrome and extramedullary atrophy Is useful for treating or alleviating the severity of a variety of diseases, disorders or conditions, including Graves' disease.

Justice

As used herein, the following definitions apply unless otherwise indicated.

The term "ABC transporter " as used herein is an ABC transporter protein or fragment thereof, wherein the protein or fragment thereof is present in vivo or in vitro, comprising at least one binding domain. The term "binding domain" as used herein means an ABC transporter domain capable of binding a modulator. See, e.g., Hwang, TC et al. , J. Gen. Physiol. (1998): 111 (3), 477-90.

The term "CFTR " as used herein refers to a cystic fibrosis trans-membrane conductivity modulator or mutant thereof, which may have modulator activity, including, but not limited to, ΔF508 CFTR and G551D CFTR For example, see http://www.genet.sickkids.on.ca/cftr/).

As used herein, the term "modulation" means an increase or decrease in activity, e.g., by a measurable amount. Compounds that increase the activity of ABC transporters, e. G., CFTR anion channels to modulate ABC transporter activity, e. G., CFTR activity, are referred to as agonists. Compounds that decrease the activity of ABC transporters, e. G., CFTR anion channels, to modulate ABC transporter activity, e. G., CFTR activity, are referred to as antagonists. Agonists interact with ABC transporters, e. G., The CFTR anion channel, to increase the ability of the receptor to convert intracellular signals in response to endogenous ligand binding. Antagonists interact with ABC transporters, e.g., CFTR, and compete with the endogenous ligand (s) or substrate (s) for the binding site (s) on the receptor such that the receptor responds to endogenous ligand binding, Thereby reducing the ability to convert.

The phrase "treating or reducing the severity of ABC transporter mediated disease" is not directly caused by treatment of ABC transporter and / or CTSR anion channel activity with ABC transporter and / or CFTR anion channel activity Both of which alleviate the symptoms of unhealthy illness. Examples of diseases in which the symptoms can be affected by ABC transporter and / or CFTR activity include, but are not limited to, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency, Deficiency, type 1 hereditary vascular edema, lipid deficiency disorders, such as familial hypercholesterolemia, type 1 kelmicronemia, unbeta lipoproteinemia, lysosomal storage diseases, such as I-cell disease / Hyperglycemia, hyperlipoproteinemia, primary hyperparathyroidism, melanoma, 1, hyperglycemia, hyperlipidemia, diabetes mellitus, mollusk polysomnia, Sandhoff / Tei-Sakes, Type II chrysler-Najar (DI), neuroblastoma diabetes insipidus, idiopathic diabetes insipidus, Sharko-maritosis syndrome, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's Spinal cord and bulbar muscular dystrophy, spinal cord and bulbar muscular dystrophy, spinal cord nucleus proliferative dystrophy and dysthymic dystrophy as well as spongiform encephalopathy such as hereditary Croucht-Jacob disease, Fabry's disease, Straussler-Shine Kard syndrome, COPD, dry eye syndrome, and Sphgenic Disease.

For the purposes of the present invention, chemical elements are identified according to the elemental periodic table (CAS version, Handbook of Chemistry and Physics, 75th Ed.). In addition, general principles of organic chemistry are described in "Organic Chemistry ", Thomas Sorrell, University Science Books, Sausolito: 1999; &Quot; March ' s Advanced Organic Chemistry ", 5th Ed., Ed. And March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

For the purposes of the present invention, chemical elements are identified according to the elemental periodic table (CAS version, Handbook of Chemistry and Physics, 75th Ed.). In addition, general principles of organic chemistry are described in "Organic Chemistry ", Thomas Sorrell, University Science Books, Sausolito: 1999; &Quot; March ' s Advanced Organic Chemistry ", 5th Ed., Ed. And March, J., John Wiley & Sons, New York: 2001.

As used herein, the term "aliphatic" includes the term alkyl, alkenyl, alkynyl, each of which is optionally substituted as described below.

As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group of from 1 to 8 carbon atoms, such as from 1 to 6 or from 1 to 4 carbon atoms. The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, n-pentyl, n-heptyl or 2-ethylhexyl. The alkyl group may be optionally substituted with one or more substituents selected from the group consisting of halo, alicyclic [e.g., cycloalkyl or cycloalkenyl], a fused ring heteroaryl such as a heterocycloalkyl or heterocycloalkenyl, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [ Examples include: (aliphatic) carbonyl, (alicyclic) carbonyl, or (bicyclic) carbonyl], nitro, cyano, amido such as (cycloalkylalkyl) carbonylamino, arylcarbonylamino (Heterocycloalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino], amino [e.g., aliphatic amino, alicyclic amino, or Substituted aliphatic amino], sulfonyl [such as aliphatic sulfonyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, alicyclic oxy, Oxy, aryloxy, heteroaryloxy, aralkyloxy , Heteroaryl, alkoxy, alkoxycarbonyl, (I.e., optionally substituted) with one or more substituents, such as alkyl, alkoxy, alkylcarbonyloxy, or hydroxy. Some examples of substituted alkyls include, but are not limited to, carboxyalkyl (e.g., HOOC-alkyl, alkoxycarbonylalkyl and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, hydroxy Alkyl, (alkoxy) alkyl, (sulfonylamino) alkyl such as (alkylsulfonylamino) alkyl, aminoalkyl, amidoalkyl, (alicyclic) alkyl, cyanoalkyl, .

As used herein, an "alkenyl" group refers to an aliphatic carbon group containing from two to eight carbon atoms (eg, 2-6 or 2-4) containing one or more double bonds. Like the alkyl group, the alkenyl group may be linear or branched. Examples of alkenyl groups include, but are not limited to, allyl, isoprenyl, 2-butenyl and 2-hexenyl. The alkenyl group may be substituted with one or more substituents such as halo, alicyclic, heterocyclic, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl such as (alicyclic) Carbonyl], nitro, cyano, acyl such as aliphatic carbonyl, alicyclic carbonyl, arylcarbonyl, heterocyclylcarbonyl or heteroarylcarbonyl, amido such as (cycloalkylalkyl) (Heterocycloalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl (heterocycloalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, , Cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphatic amino or aliphatic sulfonylamino], sulfonyl such as alkylsulfonyl, alicyclic Propylsulfonyl or aryl Alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, Heteroarylalkoxy, alkoxycarbonyl, Alkylcarbonyloxy, or hydroxy. ≪ / RTI >

As used herein, an "alkynyl" group refers to an aliphatic carbon group containing from two to eight carbon atoms (eg, 2-6 or 2-4) containing one or more triple bonds. The alkynyl group may be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. The alkynyl group is optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, For example, hydroxy, sulfo, mercapto, sulfanyl such as aliphatic sulfanyl or alicyclic sulfanyl, sulfinyl [such as aliphatic sulfinyl or alicyclic sulfinyl], sulfonyl such as aliphatic sulfonyl, Alkylsulfonyl, alkylsulfonyl, arylsulfonylsulfonyl, arylsulfonylsulfonyl, arylsulfonylsulfonyl, arylsulfonylsulfonyl, arylsulfonylsulfonyl, arylsulfonylsulfonyl, arylsulfonylsulfonyl, Heteroarylcarbonylamino, heteroarylcarbonylamino, heteroarylcarbonylamino, or heteroarylcarbonylamino, wherein said heteroarylcarbonylamino is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, Aminocarbonyl], urea, thiourea, sulfamoyl, sulfamido, alkoxycarbonyl, alkylcarbonyloxy, alicyclic, heterocyclic, aryl, heteroaryl, acyl such as (alicyclic) (Heteroaryl) oxy, or (heteroaryl) alkoxy optionally substituted with at least one substituent selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, carbonyl, amino [e.g. aliphatic amino], sulfoxy, oxo, carboxy, carbamoyl, .

As used herein, "amido" includes both "aminocarbonyl" and "carbonylamino ". These terms, when used alone or in combination with another group, refer to N (R ^X R ^Y ) -C (O) - or R ^Y C (O) - when used in an amido group, -N (R ^X) - the bottom (where, R ^X and R ^Y is -, when used therein, -C (O) -N (R X) - or ^{-N (R X) -C (O} ) As defined above). Examples of amido groups include, but are not limited to, alkylamido (e.g., alkylcarbonylamino or alkylcarbonylamino), (biphosgene) amido, (heteroaralkyl) amido, (heteroaryl) ) Alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido, or cycloalkylamido.

As used herein, an "amino" group refers to a group -NR ^X R ^Y wherein R ^X and R ^Y are independently selected from hydrogen, alkyl, cycloaliphatic, (alicyclic) aliphatic, aryl, araliphatic, (Aliphatic) aliphatic, aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (alicyclic) (Heteroaryl) carbonyl, or (heteroaromatic aliphatic) carbonyl, each of which is defined herein and is optionally substituted (heteroaryl) carbonyl, Become]. Examples of amino groups include alkylamino, dialkylamino or arylamino. When the term "amino" is not a terminal group, it is represented by -NR ^X - (R ^X is as defined above).

As used herein, an "aryl" group used alone or as part of a larger moiety in "aralkyl", "aralkoxy" or "aryloxyalkyl" refers to a monocyclic (eg, phenyl), bicyclic (For example, indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl) and tricyclic (for example, fluorenyl, tetrahydrofuranyl or tetrahydroanthracenyl, anthracenyl) Wherein the ring system is aromatic or at least one ring of the bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic ring systems include benzo-fused 2-3 membered carbocyclic rings. For example, a benzo fused group includes phenyl fused with two or more C _{4 -8} carbocyclic moieties. Aryl is an aliphatic [e.g. alkyl, alkenyl or alkynyl]; Alicyclic; (Alicyclic) aliphatic; Noncompliance; (Bicomponent aliphatic) aliphatic; Aryl; Heteroaryl; Alkoxy; (Alicyclic) oxy; (Biphenyl ring) oxy; Aryloxy; Heteroaryloxy; (Aromatic aliphatic) oxy; (Heteroaromatic aliphatic) oxy; Aroyl; Heteroaroyl; Amino; Oxo (nonaromatic carbocyclic ring of benzo fused bicyclic or tricyclic aryl); Nitro; Carboxy; Amido; Acyl [e.g., aliphatic carbonyl; (Alicyclic) carbonyl; ((Alicyclic) aliphatic) carbonyl; (Aromatic aliphatic) carbonyl; (Bicomponent) carbonyl; ((Heterocyclic) aliphatic) carbonyl; Or (heteroaromatic) carbonyl]; Sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl]; Sulfinyl [e.g., aliphatic sulfinyl or alicyclic sulfinyl]; Sulfanyl [e.g., aliphatic sulfanyl]; Cyano; Halo; Hydroxy; Mercapto; Sulfoxy; Urea; Thiourea; Sulfamoyl; Sulfamides; Or carbamoyl. ≪ / RTI > Alternatively, the aryl may be unsubstituted.

Non-limiting examples of substituted aryl include haloaryl [e.g., mono-, di (e.g. , p, m- dihaloaryl) and (trihalo) aryl]; (Carboxy) aryl such as (alkoxycarbonyl) aryl, ((aralkyl) carbonyloxy) aryl and (alkoxycarbonyl) aryl; (Amido) aryl, such as (aminocarbonyl) aryl, ((alkylamino) alkyl) aminocarbonyl) aryl, (alkylcarbonyl) aminoaryl, (arylaminocarbonyl) ) Amino) carbonyl) aryl]; Aminoaryl such as ((alkylsulfonyl) amino) aryl or ((dialkyl) amino) aryl]; (Cyanoalkyl) aryl; (Alkoxy) aryl; (Sulfamoyl) aryl [e.g., (aminosulfonyl) aryl]; (Alkylsulfonyl) aryl; (Cyano) aryl; (Hydroxyalkyl) aryl; ((Alkoxy) alkyl) aryl; (Hydroxy) aryl, ((carboxy) alkyl) aryl; (((Dialkyl) amino) alkyl) aryl; (Nitroalkyl) aryl; (((Alkylsulfonyl) amino) alkyl) aryl; ((Substituted carbonyl) carbonyl) aryl; ((Alkylsulfonyl) alkyl) aryl; (Cyanoalkyl) aryl; (Hydroxyalkyl) aryl; (Alkylcarbonyl) aryl; Alkylaryl; (Trihaloalkyl) aryl; p -amino- m- alkoxycarbonylaryl; p -amino- m -cyanoaryl; p- halo- m -aminoaryl; Or ( m - (heterocyclic) -o - (alkyl)) aryl.

As used herein, "araliphatic", e.g., "aralkyl" group is an aliphatic-substituted aryl group: A (for example, C _{1 -4} alkyl group). "Aliphatic "," alkyl ", and "aryl" are defined herein. An example of an aromatic aliphatic, such as an aralkyl group, is benzyl.

As used herein, "aralkyl" group is an alkyl group substituted with an aryl group: A (for example, C _{1 -4} alkyl group). Both "alkyl" and " aryl "are defined above. An example of an aralkyl group is benzyl. Aralkyl may be substituted with one or more substituents such as, for example, aliphatic [e.g., carboxyalkyl, hydroxyalkyl or haloalkyl, such as alkyl, alkenyl, or alkynyl including trifluoromethyl], alicyclic (Cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, Alkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido such as aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (Heterocycloalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonyl Amino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl do.

As used herein, a "bicyclic ring system" refers to an 8-12 membered (eg, 9, 10 or 11) structure that forms two rings, wherein the two rings have one or more atoms in common Bicyclic ring system includes an isocyanate (e.g., bicycloalkyl or bicycloalkenyl), a bicycloheteroaliphatic, a bicyclic aryl, and a bicyclic heteroaryl.

As used herein, an "alicyclic" group includes a "cycloalkyl" group and a "cycloalkenyl" group, each of which is optionally substituted as described below.

As used herein, a "cycloalkyl" group refers to a saturated carbocyclic, monocyclic or bicyclic (fused or bridged) ring of from 3 to 10 carbon atoms, such as from 5 to 10 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, couyl, octahydro-indenyl, decahydro-naphthyl, bicyclo [3.2.1] Bicyclo [2.2.2] octyl, bicarb [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.3.2.] Decyl, bicyclo [2.2.2] octyl, adamantyl, Carbonyl) cycloalkyl) cycloalkyl. ≪ / RTI > As used herein, a "cycloalkenyl" group refers to a non-aromatic carbocyclic ring having from 3 to 10 carbon atoms (eg, from 4 to 8 carbon atoms) having at least one double bond. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexadienyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo [2.2.2] octenyl or bicyclo [3.3.1] nonenyl. Cycloalkyl or cycloalkenyl groups may be substituted by one or more substituents such as aliphatic [e.g. alkyl, alkenyl or alkynyl], alicyclic, alicyclic, aliphatic, (Heteroaromatic) oxy, heteroaryl, heteroaroyl, amino, amido, heteroaryloxy, heteroaryloxy, (heteroaromatic) oxy, (Aliphatic) carbonylamino, (alicyclic) carbamoyl, (alicyclic) aliphatic) carbonylamino, (aryl) carbonylamino, (Heteroaryl) carbonylamino or (heteroaromatic aliphatic) carbonylamino], nitro, carboxy [such as HOOC-, alkoxycarbonyl or alkylcarbonyloxy Carbonyl, (alicyclic) aliphatic) carbonyl, (aliphatic) carbonyl, (heterocyclic) carbonyl, Carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [for example, alkylsulfonyl and arylsulfonyl], carbonyl (for example, Optionally substituted with sulfinyl [such as alkylsulfinyl], sulfanyl such as alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo or carbamoyl.

As used herein, "cyclic moiety" includes alicyclic, heterocyclic, aryl, or heteroaryl, each of which is as defined above.

As used herein, the term "heterocyclic ring" includes heterocycloalkyl groups and heterocycloalkenyl groups, each of which is optionally substituted as described below.

As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered monocyclic or bicyclic (fused or bridged) (eg, 5- to 10-membered monocyclic or bicyclic) Or more of the ring atoms are heteroatoms (e.g., N, O, S or a combination thereof). Examples of heterocycloalkyl groups are piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, iso-oxazolidin pyridyl, morpholinyl, thio know polril, octahydro-benzofuryl, octahydro-chroman-Mesnil, octahydro-thio chroman-Mesnil, octahydro in turn, octahydro-pyridinyl, deca-hydro-quinolinyl, octahydro-benzo [b ] Thiophene, 2-oxa-bicyclo [2.2.2] octyl, 1-aza- bicyclo [2.2.2] octyl, 3- aza- bicyclo [3.2.1] octyl and 2,6- -Tricyclo [3.3.1.0 ^3,7 ] nonyl. A fused heterocycloalkyl group may be fused to a phenyl moiety, such as tetrahydroisoquinoline. "Heterocycloalkenyl" group as used herein refers to a monocyclic or bicyclic (such as a 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds, and one of the ring atoms Is a heteroatom (e.g., N, O, or S). Monocyclic and bicyclic heteroaliphatic are numbered according to standard chemical nomenclature.

A heterocycloalkyl or heterocycloalkenyl group may be substituted with one or more substituents such as aliphatic (e.g., alkyl, alkenyl or alkynyl), alicyclic, alicyclic, aliphatic, Heteroaryloxy, (heteroaliphatic) oxy, aroyl, heteroaroyl, amino, heteroaryl, heteroaryl, heteroaryl, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (Aliphatic) carbonylamino, (alicyclic) carbonylamino, (alicyclic) aliphatic) carbonylamino, (aryl) carbonylamino, (Heteroaryl) carbonylamino or (heteroaromatic) carbonylamino], nitro, carboxy (e.g., HOOC-, alkoxycarbonyl or alkylcarbamoyl) (Alicyclic) carbonyl, ((alicyclic) aliphatic) carbonyl, (aromatic aliphatic) carboxy, (Heteroaromatic) carbonyl, nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl] Optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkynyl, alkynyl, alkynyl, alkynyl, have.

As used herein, a "heteroaryl" group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, wherein one or more ring atoms are heteroatoms such as N, O, S, And wherein the at least one ring of the bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo fused ring systems having two or three rings. For example, a benzofused group of 4 to 8 to restore possession hwanjok moiety (e.g., indole rijil, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo [b] furyl, benzo [b] thiophenyl , Quinolinyl or isoquinolinyl), or benzo fused with one or two. Some examples of heteroaryls include azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, Benzo [b] thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, , Furyl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl or 1,8 - It's naphthyridyl.

Although not intended to be limiting, the monocyclic heteroaryl is preferably selected from the group consisting of furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, tosolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, Thiadiazolyl, 2H-pyranyl, 4-H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl or 1,3,5-triazyl. The monocyclic heteroaryl is numbered according to standard nomenclature.

Bicyclic heteroaryls include, but are not limited to, indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furyl, benzo [ b ] thiophenyl, quinolinyl, isoquinolinyl, indole rijil, in turn isopropyl, indolyl, benzo [b] furyl, bekso [b] thiophenyl, indazolyl, benzimidazole multiple material, benz thiazolyl, Puri carbonyl, 4H- quinolinyl quality, quinolyl, isoquinolyl, sour Naphthyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl or phthalidyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

Heteroaryl is optionally substituted with one or more substituents such as aliphatic [such as alkyl, alkenyl or alkynyl]; Alicyclic; (Alicyclic) aliphatic; Noncompliance; (Bicomponent aliphatic) aliphatic; Aryl; Heteroaryl; Alkoxy; (Alicyclic) oxy; (Biphenyl ring) oxy; Aryloxy; Heteroaryloxy; (Aromatic aliphatic) oxy; (Heteroaromatic aliphatic) oxy; Aroyl; Heteroaroyl; Amino; Oxo (non-aromatic carbocyclic or heterocyclic ring of bicyclic or tricyclic heteroaryl); Carboxy; Amido; Acyl [e.g., aliphatic carbonyl; (Alicyclic) carbonyl; ((Alicyclic) aliphatic) carbonyl; (Aromatic aliphatic) carbonyl; (Bicomponent) carbonyl; ((Heterocyclic) aliphatic) carbonyl; Or (heteroaromatic) carbonyl]; Sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl]; Sulfinyl [e.g., aliphatic sulfinyl]; Sulfanyl [e.g., aliphatic sulfanyl]; Nitro; Cyano; Halo; Hydroxy; Mercapto; Sulfoxy; Urea; Thiourea; Sulfamoyl; Sulfamides; Or carbamoyl. Alternatively, the heteroaryl may be unsubstituted.

Non-limiting examples of substituted heteroaryl include (halo) heteroaryl such as mono- and di- (halo) heteroaryl; (Carboxy) heteroaryl, such as (alkoxycarbonyl) heteroaryl; Cyanoheteroaryl; Aminoheteroaryl such as ((alkylsulfonyl) amino) heteroaryl and ((dialkyl) amino) heteroaryl]; (((Alkyl) amino) alkyl) aminocarbonylheteroaryl, (((heteroaryl) amino) aminocarbonylheteroaryl, ) Carbonyl) heteroaryl, ((heterocyclic) carbonyl) heteroaryl, and ((alkylcarbonyl) amino) heteroaryl]; (Cyanoalkyl) heteroaryl; (Alkoxy) heteroaryl; (Sulfamoyl) heteroaryl such as (aminosulfonyl) heteroaryl]; (Sulfonyl) heteroaryl such as (alkylsulfonyl) heteroaryl]; (Hydroxyalkyl) heteroaryl; (Alkoxyalkyl) heteroaryl; (Hydroxy) heteroaryl; ((Carboxy) alkyl) heteroaryl; [((Dialkyl) amino) alkyl] heteroaryl; (Heteroaryl) heteroaryl; (Alicyclic) heteroaryl; (Nitroalkyl) heteroaryl; (((Alkylsulfonyl) amino) alkyl) heteroaryl; ((Alkylsulfonyl) alkyl) heteroaryl; (Cyanoalkyl) heteroaryl; (Acyl) heteroaryl, such as (alkylcarbonyl) heteroaryl; (Alkyl) heteroaryl, and (haloalkyl) heteroaryl such as trihaloalkylheteroaryl.

"Hetero aromatic aliphatic" as used herein (e.g., heteroaralkyl group) is an aliphatic substituted with a heteroaryl group: A (for example, C _{1 -4} alkyl group). "Aliphatic "," alkyl ", and "heteroaryl" are defined above.

"Heteroaralkyl" group, a, an alkyl group substituted with a heteroaryl group, as used herein: refers to (for example, C _{1 -4} alkyl group). Both "alkyl" and "heteroaryl" are defined above. Heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl, such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) Heteroaryl, heteroaryl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, (Cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heteroaryl) carbonylamino, heteroarylcarbonylamino, heteroarylcarbonylamino, Heteroarylcarbonylamino, cyano, halo, hydroxy, (lower alkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, Acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo or carbamoyl.

As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which is defined above.

As used herein, the group "acyl" is a formyl group or R ^X -C (O) - (e.g.-alkyl -C (O) -, also referred to as "alkylcarbonyl") (wherein, ^X and R "Alkyl" is as defined above). Acetyl and pivaloyl are examples of acyl groups.

As used herein, "aroyl" or "heteroaroyl" refers to aryl-C (O) - or heteroaryl-C (O) -. The aryl and heteroaryl moieties of aroyl or heteroaroyl are optionally substituted as defined above.

As used herein, an "alkoxy" group refers to an alkyl-O- group, wherein "alkyl" is as defined above.

As used herein, a "carbamoyl" group refers to a structure of the formula -O-CO-NR ^x R ^y or -NR ^x -CO-OR ^z wherein R ^x and R ^Y are as defined above and R ^Z May be an aliphatic, aryl, araliphatic, bicyclic, heteroaryl or heteroaromatic group.

As used herein, a "carboxy" group when used as a terminal group refers to -COOH, -COOR ^X , -OC (O) H, -OC (O) R ^X , , -OC (O) - or -C (O) O-.

As used herein, a "halo aliphatic" group refers to an aliphatic group substituted with one, two or three halogens. For example, the term haloalkyl includes -CF ₃ groups.

As used herein, the term "mercapto" group refers to -SH.

As used herein, a "sulfo" group refers to -SO ₃ H or -SO ₃ R ^X when used at the end, and -S (O) ₃ - when used internally.

If As used herein, the group "sulfamide" is used for the terminal when using the structure of the formula _{^{-NR X -S (O) 2 -NR}} Y R Z, within the formula -NR ^X -S (O ) ₂ -NR ^Y- , wherein R ^X , R ^Y and R ^Z are as defined above.

As used herein, a "sulfamoyl" group, used in the terminal using the formula -S (O) ₂ of the structure -NR ^x R ^y or ^x -NR -S (O) ₂ -R ^z, inside Refers to the structure of the formula -S (O) ₂ -NR ^x - or -NR ^x -S (O) ₂ -, wherein R ^x , R ^y and R ^Z are as defined above.

As used herein, a "sulfanyl" group refers to -SR ^X where R ^X is as defined above when used at the end, and -S- when used internally. Examples of sulfanyl include alkylsulfanyl.

As used herein, a "sulfinyl" group refers to the group -S (O) -R ^X where R ^X is as defined above when used at the terminus, -S (O) - .

As used herein , a "sulfonyl" group refers to -S (O) ₂ -R ^X where R ^X is as defined above when used at the end, -S (O) ₂ -.

As used herein, a "sulfoxy" group refers to -O-SO-R ^X or -SO-OR ^X where R ^X is as defined above when used at the end, OS (O) - or -S (O) -O-.

As used herein, "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

As used herein, the term "alkoxycarbonyl " included by the term carboxy refers to a group such as alkyl-O-C (O) -, either alone or in combination with another group.

As used herein, "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl- wherein alkyl is as defined above.

As used herein, "carbonyl" refers to -C (O) -.

As used herein, "oxo" refers to = O.

As used herein, "aminoalkyl" refers to the structure of the formula (R ^X R ^Y ) N-alkyl-.

As used herein, "cyanoalkyl" refers to (NC) -alkyl-.

As used herein, the term "urea" refers to the structure of the formula -NR ^X -CO-NR ^Y R ^Z , where the "thiourea" group refers to the structure -NR ^X -CS-NR ^Y R ^Z Refers to a group of the formula -NR ^X -CO-NR ^Y- or -NR ^X -CS-NR ^Y- where R ^X , R ^Y and R ^Z are as defined above when used internally .

As used herein, a "guanidino" group refers to a structure of the formula -N═C (N (R ^X R ^Y )) N (R ^X R ^Y ) wherein R ^X and R ^Y are as defined above ).

As used herein, the term "amidino" group refers to the structure of the formula -C = (NR ^X ) N (R ^X R ^Y ) wherein R ^X and R ^Y are as defined above.

In general, the term "vicinal" refers to a configuration of a group-wise substituent of two or more carbon atoms wherein the substituent is attached to an adjacent carbon atom.

In general, the term " geminal "refers to the arrangement of group-wise substituents of two or more carbon atoms, wherein the substituents are bonded to the same carbon atom.

The terms " at the end "and" inside "refer to the position of a group within a substituent. When a group is present at the end of a substituent that is not further attached to the remainder of the chemical structure, the group is at the terminus. Carboxyalkyl, i.e. R ^X O (O) C-alkyl, is an example of a carboxy group used at the terminus. When a group is present in the middle of a substituent for the terminal of a substituent bound to the remainder of the chemical structure, the group is internal. Alkyl-O (O) -aryl- or alkyl-O (CO) -aryl-) alkylcarboxy (e.g., alkyl-C (O) O- or alkyl- Is an example of a carboxy group used therein.

As used herein, the term "amidino" group refers to the structure of the formula -C = (NR ^X ) N (R ^X R ^Y ) wherein R ^X and R ^Y are as defined above.

As used herein, "cyclic group" includes monocyclic, bicyclic, and tricyclic ring systems, including alicyclic, heterocyclic, aryl, or heteroaryl (each as defined above).

As used herein, "bridged bicyclic ring system" refers to a bicyclic, bicyclic, bicyclic, or bicyclic alicyclic ring system, wherein the ring is bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] Bicyclo [3.2.3] nonyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 2,6-dioxa-tricyclo [3.3.1.03,7] nonyl. A bridged bicyclic ring system may contain one or more substituents such as, for example, alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, Heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, aryloxy, heteroaryloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaryloxy, (Cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonyl, aralkylcarbonylamino, alkylcarbonylamino, alkylcarbonylamino, cycloalkylcarbonylamino, Heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, haloalkyl, and the like. The term " alkyl " Which may be optionally substituted with halogen, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo or carbamoyl.

As used herein, "aliphatic chain" refers to aliphatic groups that are branched or linear (e.g., alkyl groups, alkenyl groups, or alkynyl groups). The linear aliphatic chain has the structure - (CH ₂ ) _v -, wherein v is 1 to 6. A branched aliphatic chain is a linear aliphatic chain substituted with one or more aliphatic groups. Branched aliphatic chains have a structure of the formula - [CHQ] _v -, wherein Q is hydrogen or aliphatic, but Q is aliphatic in at least one example. The term aliphatic chain includes alkyl chains, alkenyl chains and alkynyl chains wherein alkyl, alkenyl and alkynyl are as defined above.

The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted ". As described herein, compounds of the present invention may be optionally substituted with one or more substituents, as generally described above, or as exemplified by a particular class, subclass, and species of the invention. As described herein, R ₁ , R ₂ , R _3, and R ₄ and other variables contained therein in Formula I include certain groups such as alkyl and aryl. Unless otherwise noted, each of the specific groups for variables R ₁ , R ₂ , R _3, and R ₄ and any other variables contained therein may be optionally substituted with one or more substituents described herein. Each substituent of a particular group is optionally further substituted with 1 to 3 of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, haloalkyl and alkyl. For example, the alkyl group may be substituted with alkylsulfanyl and the alkylsulfanyl may be optionally substituted with 1 to 3 of halo, cyano, oxoalkoxy, hydroxy, amino, nitro, aryl, have. As a further example, the cycloalkyl moiety of a (cycloalkyl) carbonylamino may be optionally substituted with 1 to 3 of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl and alkyl. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups may form a ring together with the atom (s) to which they are bonded.

In general, the term " substituted " refers to the replacement of a hydrogen radical in a given structure with the radical of the specified substituent, whether or not the term "optionally" precedes it. Particular substituents are described above and in the description of the compounds below and their examples. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and in any given structure, when more than one position may be substituted with one or more substituents selected from the indicated group, Position. ≪ / RTI > A ring substituent, for example, heterocycloalkyl, may be attached to another ring, for example, cycloalkyl, to form a spiro-bicyclic ring system, for example, where both rings share a common atom. Those skilled in the art will recognize that combinations of contemplated substituents according to the invention are combinations that form stable or chemically feasible compounds.

The term "below " as used herein refers to an integer equal to or less than zero or the number following the term. For example, "3 or less" means any of 0, 1, 2, and 3.

As used herein, the term "stable or chemically feasible" means that when treated with conditions that make it possible to prepare, detect and preferably recover the compound, use it for one or more of the purposes described herein, . ≪ / RTI > In some embodiments, the stable compound or chemically feasible compound is substantially unchanged if it is maintained for at least one week in the absence of moisture or other chemically reactive conditions at a temperature of 40 占 폚 or lower.

As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on a treated patient, and is typically determined on the basis of the age, surface area, weight and condition of the patient. The correlation of dose to animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep . , ≪ / RTI > 50: 219 (1966). The body surface area can be roughly measured from the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

Unless otherwise indicated, structures described herein include all isomeric forms of the structure (e.g., enantiomers, diastereomers and geometric isomers and / or geometric isomers), such as R and S forms for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) isomers. Therefore, enantiomers, diastereomers and geometric isomers (or isomeric) mixtures of the compounds of the present invention, as well as single stereochemically isomeric forms, are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention. In addition, unless otherwise stated, the structures described herein are also meant to include different compounds only in the presence of one or more isotopically enriched elements. For example, compounds having the structure of the present invention, except for the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with ¹³ C- or ¹⁴ C-rich carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical instruments or probes in biological assays.

compound

The compounds of the present invention are useful modulators of ABC transporters and are useful in the treatment of ABC transport mediated diseases.

A. General compounds

The present invention includes a compound of formula I or a pharmaceutically acceptable salt thereof.

Formula I

In the above formula (I)

Each R ₁ is optionally substituted C _{1 -6} aliphatic, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted C _{3 -10} cycloaliphatic, an optionally substituted 3-to 10 restore possession hwanjok, carboxy [e.g. Amino, halo, or hydroxy, with the proviso that at least one R < ₁ > is an optionally substituted alkyl group optionally substituted at the 5 or 6 position of the pyridyl ring, Optionally substituted heteroaryl, optionally substituted heteroaryl, optionally substituted aryl or optionally substituted heteroaryl,

R ₂ are each a hydrogen, an optionally substituted C _{1 -6} aliphatic, an optionally substituted C _{3 -6} aliphatic, optionally substituted phenyl or optionally substituted heteroaryl,

R ₃ and R _'3 are each together with the carbon atom to which they are attached, forms an optionally substituted C _{3 -7} cycloaliphatic or an optionally substituted repeat possession hwanjok,

R < ₄ > are each optionally substituted aryl or optionally substituted heteroaryl,

n is 1, 2, 3 or 4, respectively.

In another aspect, the invention includes a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Ia

In the above formula (Ia)

One of G < _{1 >} and G < ₂ > is nitrogen and the other is carbon,

R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ and n are as defined above.

Specific mode

A. Substituent R ₁

R ₁ each independently represent an optionally substituted C _{1 -6} aliphatic, optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted C _{3 -10} won cycloaliphatic, an optionally substituted 3-to 10 restore possession hwanjok, carboxy For example, hydroxycarbonyl or alkoxycarbonyl, amido [for example, aminocarbonyl] amino, halo, or hydroxy.

In some embodiments, one of R ₁ is optionally substituted C _{1 -6} aliphatic. In some examples, one of R ₁ is optionally substituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, or an optionally substituted C _{2 -6-alkynyl.} In some examples, one of R ₁ is C _{1 -6} alkyl, C _{2 -6} alkenyl or C _2-6 alkynyl.

In some embodiments, one R < ₁ > is aryl or heteroaryl having 1, 2 or 3 substituents. In some instances, one R < _{1 >} is a monocyclic aryl or heteroaryl. In some embodiments, R < ₁ > is aryl or heteroaryl having 1, 2 or 3 substituents. In some instances, R < _{1 >} is a monocyclic aryl or heteroaryl.

In some embodiments, at least one R ₁ is optionally substituted aryl or optionally substituted heteroaryl and R ₁ is attached to the core structure at the 6-position of the pyridine ring.

In some embodiments, at least one R ₁ is optionally substituted aryl or optionally substituted heteroaryl and R ₁ is attached to the core structure at the 5 position of the pyridine ring.

In some embodiments, one R < ₁ > is phenyl having up to three substituents. In some embodiments, R < ₁ > is phenyl having up to 3 substituents.

In some embodiments, one R < ₁ > is a heteroaryl ring having up to three substituents. In certain embodiments, one R < ₁ > is a monocyclic heteroaryl ring having up to three substituents. In another embodiment, one R < ₁ > is a bicyclic heteroaryl ring having up to three substituents. In some embodiments, R < ₁ > is a heteroaryl ring having up to three substituents. In certain embodiments, R < ₁ > is a monocyclic heteroaryl ring having up to three substituents. In another embodiment, R < ₁ > is a bicyclic heteroaryl ring having up to three substituents.

In some embodiments, one R < ₁ > is carboxy [e.g., hydroxycarbonyl or alkoxycarbonyl]. Or one R < ₁ > is an amido such as an aminocarbonyl. Or one R < ₁ > is amino. Or halo. Or cyano. Or hydroxyl.

In certain embodiments, R ₁ is hydrogen, methyl, ethyl, i-propyl, t-butyl, cyclopropyl, t- butoxycarbonyl, CF _3, OCF _3, CN, a hydroxyl, or amino. In some instances, R ₁ is hydrogen, methyl, methoxy, F, CF _3, or OCF ₃ . In some instances, R < ₁ > may be hydrogen. Alternatively, R < ₁ > may be methyl. Alternatively, R ₁ may be CF ₃ . Alternatively, R < ₁ > may be methoxy.

In some embodiments, R ₁ is halo, oxo, or an optionally substituted aliphatic, alicyclic, heterocyclic, amino [eg (aliphatic) amino], amido such as aminocarbonyl, carbonyl, and ((aliphatic) _2amino) carbonyl], carboxy [e.g., alkoxycarbonyl and hydroxycarbonyl], sulfamoyl [e.g., aminosulfonyl, ((aliphatic) _2amino) sulfonyl, (( Alicyclic) aliphatic) aminosulfonyl and ((alicyclic) amino) sulfonyl], cyano, alkoxy, aryl, heteroaryl such as monocyclic heteroaryl and bicycloheteroaryl, sulfonyl such as aliphatic Substituted with up to three substituents selected from the group consisting of halogen, sulfonyl or sulfonyl, sulfinyl [e.g. aliphatic sulfinyl], aroyl, heteroaroyl, or heterocyclic carbonyl.

In some embodiments, R &_lt; ₁ > is substituted with halo. Examples of R < ₁ > substituents include F, Cl and Br. In some instances, R < ₁ >

In some embodiments, R < _{1 >} is optionally substituted with a substituted aliphatic. Examples of R ₁ substituents include, but are not limited to, optionally substituted alkoxy aliphatic, heterocyclic aliphatic, aminoalkyl, hydroxyalkyl, (heterocycloalkyl) aliphatic, alkylsulfonyl aliphatic, alkylsulfonylamino aliphatic, , Or an alkylcarbonyl aliphatic.

In some embodiments, R < _{1 >} is optionally substituted amino. Examples of R ₁ substituents include aliphatic carbonylamino, aliphatic amino, arylamino, or aliphatic sulfonylamino.

In some embodiments, R < ₁ > is substituted with a sulfonyl. Examples of R < ₁ > substituents include, but are not limited to, heterocyclic ring sulfonyl, aliphatic sulfonyl, aliphatic aminosulfonyl, aminosulfonyl, aliphatic carbonylaminosulfonyl, alkoxyalkylheterocycloalkylsulfonyl, alkylheterocycloalkylsulfonyl, (Cycloalkyl) aminosulfonyl, (heterocycloalkyl) alkylaminosulfonyl, and heterocycloalkylsulfonyl.

In some embodiments, R < ₁ > is substituted with carboxy. Examples of R < ₁ > substituents include alkoxycarbonyl and hydroxycarbonyl.

In some embodiments, R < ₁ > is substituted with an amide. Examples of R ₁ substituents include alkylaminocarbonyl, aminocarbonyl, ((aliphatic) ₂ amino) carbonyl and [((aliphatic) amino aliphatic) amino] carbonyl.

In some embodiments, R < ₁ > is substituted with carbonyl. Examples of R < ₁ > substituents include arylcarbonyl, alicyclic carbonyl, heterocyclic carbonyl, and heteroarylcarbonyl.

In some embodiments, R < ₁ > is hydrogen. In certain embodiments, R ₁ is -Z ^A R ₅ [wherein Z ^A is each independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain (wherein 2 carbon units of no more than the Z ^A is optionally -CO-, -CS-, -CONR ^A- , -CONR ^A NR ^A -, -CO ₂ -, -OCO-, -NR ^A CO ₂ -, -O-, -NR ^A CONR ^A -, - OCONR ^A- , -NR ^A NR ^A- , -NR ^A CO-, -S-, -SO-, -SO ₂ -, -NR ^A -, -SO ₂ NR ^A -, -NR ^A SO ₂ - -NR < ^{A &} _gt; SO2NR < ^A > -). R ₅ is independently R ^A , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ . R ^A is independently C _{1 -8} aliphatic, cycloaliphatic, clothing possession hwanjok, aryl, or heteroaryl, each of which is optionally substituted with one, two, or three R ^D. Each R ^D is independently selected from the group consisting of -Z ^D R ₉ wherein Z ^D is independently a bond or an optionally substituted branched or linear C _1-6 aliphatic chain wherein two or fewer carbon units of Z ^D are optionally independently -CO-, -CS-, -CONR ^E -, -CONR ^E NR ^E -, -CO ₂ -, -OCO-, -NR ^E CO ₂ -, -O-, -NR ^E CONR ^E -, -OCONR ^E -, -NR ^E NR ^E -, -NR ^E CO-, -S-, -SO-, -SO ₂ -, -NR ^E -, -SO ₂ NR ^E -, -NR ^E SO ₂ - ^E SO ₂ NR ^E -). Each R ₉ is independently R ^E , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ . R ^E are each independently hydrogen, optionally substituted C _{1 -8} aliphatic, optionally substituted cycloaliphatic, an optionally substituted repeat possession hwanjok, aryl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, R ^D are each -Z ^D R ₉ [where independently, Z ^D are each independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain (wherein no more than 2 carbon of Z ^D units are optionally independently -O-, -NHC (O) -, -C (O) NR E -, -SO 2 -, -NHSO 2 -, -NHC (O) -, -NR E SO 2 -, - SO ₂ NH-, -SO ₂ NR ^E -, -NH-, or -C (O) O-. In some embodiments, one carbon unit of Z ^D is replaced by -O-. Or -NHC (O) -. Or -C (O) NR ^E -. Or -SO ₂ -. Or -NHSO ₂ -. Or -NHC (O) -. Or -SO-. Or -NR ^E SO ₂ -. Or, it is substituted by -SO ₂ NH-. Or -SO ₂ NR ^E -. Or -NH-. Or -C (O) O-.

In some embodiments, R ₉ is hydrogen. In some embodiments, R < ₉ > is an independently optionally substituted aliphatic. In some embodiments, R < ₉ > is an optionally substituted alicyclic group. Or an optionally substituted repeat ring. Or is optionally substituted aryl. Or an optionally substituted heteroaryl. Or halo.

In certain embodiments, one of R ₁ is optionally substituted with aryl or heteroaryl, each one, two or three R ^D (wherein, R ^D are the same as defined above).

In some embodiments, one R < ₁ > is carboxy [e.g., hydroxycarbonyl or alkoxycarbonyl]. Or one R < ₁ > is an amido such as an aminocarbonyl. Or one R < ₁ > is amino. Or halo. Or cyano. Or hydroxyl.

In some embodiments, one R ₁ attached at the 5 or 6 position of the pyridyl ring is aryl or heteroaryl, optionally substituted with one, two, or three R ^D , wherein R ^D is as defined above. In some embodiments, one R < ₁ > attached at the 5 or 6 position of the pyridyl ring is optionally substituted with one, two or three R < ^d >, wherein R < ^D > In some embodiments, one R ₁ attached at the 5 or 6 position of the pyridyl ring is a heteroaryl optionally substituted with one, two, or three R ^D. In some embodiments, one R ₁ attached to the 5 or 6 position of the pyridyl ring is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur to be. In another embodiment, the 5 or 6 membered heteroaryl is substituted with one R ^D.

In some embodiments, one R ₁ attached at the 5 or 6 position of the pyridyl ring is phenyl substituted with one R ^D. In some embodiments, one R < ₁ > attached at the 5 or 6 position of the pyridyl ring is phenyl substituted with 2 R < ^{D &} gt ;. In some embodiments, one R < ₁ > attached at the 5 or 6 position of the pyridyl ring is phenyl substituted with 3 R < ^{D &} gt ;.

(Z-1) 또는

(Z-2)[여기서, W₁은 -C(O)-, -SO₂-, 또는 -CH₂-이고; D는 H, 하이드록실, 또는 지방족, 지환족, 알콕시 및 아미노로부터 선택된 임의로 치환된 그룹이며; R^D는 위에서 정의한 바와 같다]으로 나타낸다.In some embodiments, R < ₁ >

(Z-1) or

(Z-2) wherein W ₁ is -C (O) -, -SO ₂ -, or -CH ₂ -; D is H, hydroxyl, or an optionally substituted group selected from aliphatic, cycloaliphatic, alkoxy and amino; R ^D is as defined above.

In some embodiments, W < ₁ > is -C (O) -. Or W ₁ is -SO ₂ -. Or W ₁ is -CH ₂ -.

In some embodiments, D is OH. Or D is an optionally substituted C _{1 -6} aliphatic or optionally substituted C ₃ -C ₈ cycloaliphatic. Or D is optionally substituted alkoxy. Or D is optionally substituted amino.

(여기서, A 및 B는 각각 독립적으로 H, 임의로 치환된 C_{1 -6} 지방족, 임의로 치환된 C₃-C₈ 지환족이거나; A와 B는 함께 임의로 치환된 3-7원 복소지환족 환을 형성한다)이다.In some instances, D is

Wherein A and B are each independently H, an optionally substituted C _{1 -6} aliphatic, optionally substituted C ₃ -C ₈ cycloaliphatic, or A and B together form a 3-7 membered heterocyclic ring optionally substituted Lt; / RTI >

In some embodiments, A is H, B is a C _{1 -6} aliphatic group optionally substituted. In some embodiments, B is substituted with 1, 2, or 3 substituents. Or A and B are both H. Exemplary substituents include optionally substituted groups selected from oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, dialkylamino, or cycloaliphatic, heterocyclic, aryl, and heteroaryl.

In some embodiments, A is H, B is a C _{1 -6} aliphatic group optionally substituted. Or A and B are both H. Exemplary substituents include oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, and optionally substituted bicyclic rings.

In some embodiments, B is oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, optionally substituted C _{1 -6} alkyl, or alicyclic, carrying clothing hwanjok, aryl, and an optionally substituted group selected from heteroaryl, to be. In some embodiments, B is oxo, C _{1 -6} alkyl, hydroxy, hydroxy - (C _{1 -6)} alkyl, (C _{1 -6)} alkoxy, (C _{1 -6)} alkoxycarbonyl (C _{1 -6)} alkyl, C _{3 -8} cycloaliphatic, 3-8 restore possession hwanjok is substituted with phenyl, and a 5-10 membered heteroaryl. In one example, B is a C _{1 -6} alkyl optionally substituted by a substituted phenyl.

In some embodiments, A and B together form an optionally substituted 3-7 membered heterocyclic ring. In some instances, the bicyclic ring is optionally substituted with 1, 2, or 3 substituents. Exemplary such rings include optionally substituted pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl. Exemplary substituents for such rings include halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl (e.g., alkylcarbonyl), amino, amido and carboxy. In some embodiments, the substituent is halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, or carboxy.

In some embodiments, R ^D is hydrogen, halo, or an optionally substituted group selected from aliphatic, cycloaliphatic, amino, hydroxy, alkoxy, carboxy, amido, carbonyl, cyano, aryl, and heteroaryl. In some examples, R ^D is hydrogen, halo, optionally substituted C _{1 -6} aliphatic, or an optionally substituted alkoxy. In some examples, R ^D is hydrogen, F, Cl, an optionally substituted C _{1 -6} alkyl, or an optionally substituted -O (C _{1 -6} alkyl). Examples of R ^D are hydrogen, F, Cl, methyl, ethyl, i -propyl, t -butyl, -OMe, -OEt, i -propoxy, t-butoxy, CF ₃ or -OCF ₃ . In some instances, R ^D is hydrogen, F, methyl, methoxy, CF ₃ , or -OCF ₃ . R ^D can be hydrogen. R ^D can be F. R ^D can be methyl. R ^D can be methoxy.

(Z)[여기서, W₁는 -C(O)-, -SO₂-, 또는 -CH₂-이고; A 및 B 각각은 독립적으로 H, 임의로 치환된 C_{1 -6} 지방족, 임의로 치환된 C₃-C₈ 지환족이거나; A와 B는 함께 임의로 치환된 3-7원 복소지환족 환을 형성한다]으로 나타낸다.In some embodiments, R < ₁ >

(Z) wherein W ₁ is -C (O) -, -SO ₂ -, or -CH ₂ -; A and B each independently represent H, an optionally substituted C _{1 -6} aliphatic, an optionally substituted C ₃ -C ₈ cycloaliphatic or; A and B together form an optionally substituted 3-7 membered heterocyclic ring.

In some embodiments, the pyridyl ring with one R ₁ is an optionally substituted alicyclic or heterocyclic possession hwanjok with 1, 2, or 3 R ^D, each coupled to the 5 position or 6-position [where, R ^D is -Z ^D R ₉ (wherein, Z ^D are each independently a bond or an optionally branched or linear C _{1 -6} aliphatic chain-substituted, 2 or fewer carbon units of Z ^D is optionally independently -CO-, -CS-, -CONR ^E -, -CONR ^E NR ^E -, -CO ₂ -, -OCO-, -NR ^E CO ₂ -, -O-, -NR ^E CONR ^E -, -OCONR ^E -, -NR ^E NR ^E -, -NR ^E CO-, -S-, -SO-, -SO ₂ -, -NR ^E -, -SO ₂ NR ^E -, -NR ^E SO ₂ -, or -NR ^E SO ₂ NR ^E - ₉ are independently R ^E, _{halo, -OH, -NH 2, -NO 2} , -CN, -CF 3, or -OCF _3, and, R ^E is independently hydrogen, optionally substituted C _{1 -8} aliphatic, optionally A substituted cycloalkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl.

In some instances, one R ₁ attached at the 5 or 6 position of the pyridyl ring is an optionally substituted C ₃ -C ₈ alicyclic.

In some embodiments, one R ₁ attached at the 5 or 6 position of the pyridyl ring is an optionally substituted C ₃ -C ₈ cycloalkyl or an optionally substituted C ₃ -C ₈ cycloalkenyl.

In some embodiments, one R ₁ attached at the 5 or 6 position of the pyridyl ring is C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkenyl. Examples of cycloalkyl and cycloalkene include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

In some embodiments, R < ₁ >

In some instances, R ₁ is selected from the following formulas:

B. Substituent R ₂

R < ₂ > may each be hydrogen. R ₂ may be an optionally substituted group selected from C _{1 -6} aliphatic, C _{3 -6} alicyclic, phenyl and heteroaryl, respectively.

In some embodiments, R ₂ is a C _{1 -6} aliphatic optionally substituted with 1, 2 or 3 halo, C _{1 -2} aliphatic or alkoxy. In some instances, R ₂ may be substituted methyl, ethyl, propyl, or butyl. In some instances, R ₂ can be methyl, ethyl, propyl, or butyl.

In some embodiments, R ₂ is hydrogen.

C. Substituents R & lt; ₃ & R ' ₃

R ₃ and R _'3 are formed each with the carbon atoms to which they are attached, C _{3 -7} alicyclic or heterocyclic possession hwanjok (each of which is optionally substituted with one, two or three substituents). In some embodiments, R ₃ and R _'3 together with the carbon atom to which they are attached, C _{3 -7} alicyclic or C _{3 -7} clothing possession hwanjok [each of which is 1, 2 or 3 -Z ^B R ₇ (wherein , Each Z ^B is independently a bond or an optionally substituted branched or linear C _{1 -4} aliphatic chain and two or fewer carbon units of Z ^B are optionally and independently optionally replaced by -CO-, -CS-, -CONR ^B -, -CONR ^B NR ^B -, -CO ₂ -, -OCO-, -NR ^B CO ₂ -, -O-, -NR ^B CONR ^B -, -OCONR ^B -, -NR ^B NR ^B -, -NR ^{B CO-, -S-, -SO-, -SO} 2 -, -NR B -, -SO 2 NR B -, -NR B SO 2 - or -NR ^B SO ₂ NR ^B - being replaced by; R ₇ They are each independently selected from R ^B, _{halo, -OH, -NH 2, -NO 2} , -CN, -CF 3, or -OCF _3, and; R ^B is independently hydrogen, optionally substituted C _{1 -8} aliphatic, Optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl,

In some embodiments, R ₃ and R ' ₃ together with the carbon atoms to which they are attached form a 3, 4, 5, or 6 membered cycloaliphatic group optionally substituted with 1, 2, or 3 substituents. In some instances, R ₃ , R ' ₃ and the carbon atom to which they are attached form an optionally substituted cyclopropyl group. In some alternative embodiments, R ₃ , R ' ₃ and the carbon atom to which they are attached form an optionally substituted cyclobutyl group. In some other embodiments, R ₃ , R ' ₃ , and the carbon atom to which they are attached form an optionally substituted cyclopentyl group. In other embodiments, R ₃ , R ' _3, and the carbon atom to which they are attached form an optionally substituted cyclohexyl group. In a further embodiment, R ₃ , R ' _3, and the carbon atom to which they are attached, form an unsubstituted cyclopropyl.

In some embodiments, R ₃ and R ' ₃ together with the carbon atoms to which they are attached form an optionally substituted 5, 6, or 7 membered heterocyclic ring. In another embodiment, R ₃ and R ' ₃ together with the carbon atom to which they are attached form an optionally substituted tetrahydropyranyl group.

In some embodiments, R ₃ and R ' ₃ together with the carbon atoms to which they are attached form an unsubstituted C _3-7 alicyclic or unsubstituted heterocyclic ring. In some instances, R ₃ and R ' ₃ together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, unsubstituted cyclopentyl, or unsubstituted cyclohexyl.

D. Substituent R ₄

R < ₄ > are each independently optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, R < ₄ > is a 6 to 10 membered (e.g., 7 to 10 membered) aryl optionally substituted with 1, 2 or 3 substituents. Examples of R < ₄ > include optionally substituted benzene, naphthalene, or indene. Alternatively, examples of R < ₄ > may be optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted indenyl.

In some embodiments, R < ₄ > is an optionally substituted heteroaryl. Examples of R ₄ include monocyclic and bicyclic heteroaryls, such as benzo fused ring systems wherein the phenyl is fused to one or two 4-8 membered heterocyclic rings.

In some embodiments, R < ₄ > is aryl or heteroaryl, each optionally substituted with one, two, or three-Z < ^C > R < _{8 &} gt ;. In some embodiments, R < ₄ > is aryl optionally substituted with one, two, or three-Z < ^C > R < _{8 &} gt ;. In some embodiments, R < ₄ > is phenyl optionally substituted with one, two, or three-Z < ^C > R < _{8 &} gt ;. Or, R ₄ is heteroaryl optionally substituted with one, two or three R ^C -Z _8. Z ^C are each independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain [wherein no more than two carbon atoms of the Z ^C is optionally independently -CO-, -CS-, -CONR ^C -, -CONR ^C NR ^C -, -CO ₂ -, -OCO-, -NR ^C CO ₂ -, -O-, -NR ^C CONR ^C -, -OCONR ^C -, -NR ^C NR ^C -, -NR ^C CO -, -S-, -SO-, -SO ₂ -, -NR ^C -, -SO ₂ NR ^C -, -NR ^C SO ₂ -, or -NR ^C SO ₂ NR ^C -. R ₈ is each independently R ^C , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ . R ^C is independently hydrogen, optionally substituted C _{1 -8} aliphatic, optionally substituted cycloaliphatic, an optionally substituted repeat possession hwanjok, aryl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, the two -Z ^C R ₈ , together with the carbon to which they are attached, are independently selected from the group consisting of three or less rings selected from the group consisting of O, NH, NR ^C, and S (wherein R ^C is defined herein) Forming a 4-8 membered saturated, partially saturated or aromatic ring having an atom.

In some embodiments, R < ₄ > is selected from the following formulas:

E. Exemplary Compound Classes

In some embodiments, R < _{1 >} is an optionally substituted cyclic group bonded to the core structure at the 5 or 6 position of the pyridine ring.

In some instances, R < _{1 >} is an optionally substituted aryl attached to the 5 position of the pyridine ring. In another example, R < _{1 >} is an optionally substituted aryl attached to the 6-position of the pyridine ring.

In a further example, R < _{1 >} is an optionally substituted heteroaryl attached at the 5 position of the pyridine ring. In another embodiment, R < _{1 >} is an optionally substituted heteroaryl attached at the 6 position of the pyridine ring.

In another embodiment, R < _{1 >} is an optionally substituted alicyclic or optionally substituted bicyclic ring attached at the 5 or 6 position of the pyridine ring.

Accordingly, another aspect of the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

(II)

In the above formula (II)

R ₁ , R ₂ , R ₃ , R ' ₃ , and R ₄ are as defined in formula (I).

In some embodiments, R ₁ is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 R ^D , wherein R ^D is Z ^D R ₉ , wherein Z ^D is a branched or linear C _{1 -6} aliphatic chains and two or fewer carbon units of Z ^D are optionally and independently replaced by -CO-, -CS-, -CONR ^E -, -CONR ^E NR ^E -, -CO ₂ -, -OCO-, --NR ^E CO ₂ -, -O-, -NR ^E CONR ^E -, -OCONR ^E -, -NR ^E NR ^E -, -NR ^E CO-, -S-, -SO-, -SO ₂ -, - NR ^E -, -SO ₂ NR ^E -, -NR ^E SO ₂ -, or -NR ^E SO ₂ NR ^E -; Each R ₉ is independently R ^E , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ ; R ^E are each independently hydrogen, optionally substituted C _{1 -8} aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted repeat possession hwanjok, optionally substituted aryl, or optionally a heteroaryl substituted} a.

In some embodiments, R < ₁ > is an alicyclic or heterocyclic ring optionally substituted with one, two, or three R < ^d >, wherein R < ^D >

Another aspect of the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

(III)

In formula (III) above,

R ₁ , R ₂ , R ₃ , R ' ₃ , and R ₄ are as defined in formula (I).

In some embodiments, R ₁ is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 R ^D , wherein R ^D is -Z ^D R ₉ wherein Z ^D is each independently a bond or an optionally substituted branch or linear C _{1 -6} aliphatic chain, and the two carbon units of Z ^D is less than or optionally independently ^{-CO-, -CS-, -CONR E -,} -CONR E NR E -, -CO 2 -, - -CO-, -NR ^E CO ₂ -, -O-, -NR ^E CONR ^E -, -OCONR ^E -, -NR ^E NR ^E -, -NR ^E CO-, -S-, -SO-, -SO ₂ -, -NR ^E -, -SO ₂ NR ^E -, -NR ^E SO ₂ -, or -NR ^E SO ₂ NR ^E -; Each R ₉ is independently R ^E , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ ; And each R ^E is independently hydrogen, an optionally substituted C _1-8 aliphatic group, an optionally substituted alicyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl, or an optionally substituted heteroaryl.

In some embodiments, R < ₁ > is an alicyclic or heterocyclic ring optionally substituted with one, two, or three R < ^d >, wherein R < ^D >

In another aspect, the invention includes a compound of formula (IV) or a pharmaceutically acceptable salt thereof.

Formula IV

In the above formula (IV)

R ₂ , R ₃ , R ' ₃ , and R ₄ are as defined in Formula I.

R ^D is -Z ^D R ₉ wherein Z ^D is independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain and wherein two or fewer carbon units of Z ^D are optionally independently replaced by -CO- , -CS-, -CONR ^E -, -CONR ^E NR ^E -, -CO ₂ -, -OCO-, -NR ^E CO ₂ -, -O-, -NR ^E CONR ^E -, -OCONR ^E - NR ^{E E} -, -NR ^E CO-, -S-, -SO-, -SO ₂ -, -NR ^E -, -SO ₂ NR ^E -, -NR ^E SO ₂ -, or -NR ^E SO ₂ NR ^E -. ≪ / RTI >

R ₉ is independently R ^E , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ .

R ^E are each independently hydrogen, optionally substituted C _{1 -8} aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted repeat possession hwanjok, aryl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, Z ^D are independently a bond or an optionally substituted branched or linear C _{1 -6} one carbon units of an aliphatic chain, Z ^D is ^{_{-SO 2 -, -CONR E -,}} - NR E SO 2 -, or -SO ₂ NR ^E -. For example, Z ^D is an optionally substituted branched or linear C _{1 -6} aliphatic chain, and one carbon unit of Z ^D is optionally replaced by -SO ₂ -. In another example, R < ₉ > is an optionally substituted heteroaryl or an optionally substituted bicyclic ring. In a further example, R < ₉ > is an optionally substituted bicyclic ring having 1 to 2 nitrogen atoms and R < ₉ > is bonded directly to -SO < ₂ >

In another aspect, the invention includes a compound of formula Va or Vb, or a pharmaceutically acceptable salt thereof.

The formula Va

The compound of formula Vb

In the above formulas Va and Vb,

T is an optionally substituted C _{1 -2} aliphatic chain wherein each carbon unit is -CO-, -CS-, -COCO-, -SO ₂ -, -B (OH) -, or -B (O _{Lt; /} RTI > is independently optionally substituted by _{1 - 6} alkyl)) -

R ₁ 'and R ₁ "are each independently a bond or an optionally substituted C _{1 -6} aliphatic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 3- to 10-membered cycloaliphatic, optionally substituted 3- 10-membered heterocyclic ring, carboxy, amido, amino, halo, or hydroxy,

R ^D1 is bonded to a 3 "or 4" carbon,

R ^D1 and R ^D2 -Z is R ^D, each ₈ [Here, Z ^D are independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain, two carbon units ^of Z ^D is less than or optionally independently -CO-, -CS-, -CONR ^E -, -CONR ^E NR ^E -, -CO ₂ -, -OCO-, -NR ^E CO ₂ -, -O-, -NR ^E CONR ^E -, -OCONR ^E -, -NR ^E NR ^E -, -NR ^E CO-, -S-, -SO-, -SO ₂ -, -NR ^E -, -SO ₂ NR ^E -, -NR ^E SO ₂ - ^E SO ₂ NR ^E - is replaced by a - a,

R ₉ is independently R ^E , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ ,

R ^D1 and R ^D2 together with the atom to which they are attached form a 3-8 membered saturated, partially unsaturated or aromatic ring having up to three ring members independently selected from the group consisting of O, NH, NR ^E and S and,

R ^E are each independently hydrogen, optionally substituted C _{1 -8} aliphatic, optionally substituted cycloaliphatic, an optionally substituted repeat possession hwanjok, aryl, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, T is optionally substituted -CH ₂ -. In some other embodiments, T is optionally substituted -CH ₂ CH ₂ -.

In some embodiments, T is -Z ^E R ₁₀ [wherein, Z ^E are each independently a bond or an optionally substituted branched or linear C _{1 -6} aliphatic chain, two carbon units of no more than the Z ^E is optionally independently -CO-, -CS-, -CONR ^F- , -CONR ^F NR ^F -, -CO ₂ -, -OCO-, -NR ^F CO ₂ -, -O-, -NR ^F CONR ^F -, -OCONR ^F -, -NR ^F NR ^F -, -NR ^F CO-, -S-, -SO-, -SO ₂ -, -NR ^F- , -SO ₂ NR ^F -, -NR ^F SO ₂ - It is replaced by - NR ^F SO ₂ ^F; R ₁₀ is independently R ^F , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ ; R ^F is optionally substituted with independently hydrogen, optionally substituted C _{1 -8} aliphatic, optionally substituted cycloaliphatic, an optionally substituted repeat possession hwanjok, optionally substituted aryl, or optionally a heteroaryl substituted. In one example, Z ^E is -O-.

In some embodiments, R ₁₀ is optionally substituted C _{1 -6} alkyl, optionally substituted C _{2 -6} alkenyl, may be optionally substituted with C _{3 -7} cycloaliphatic, or an optionally substituted C _{6 -10} aryl group. In one embodiment, R ₁₀ is methyl, ethyl, i -propyl, or t -butyl.

In some embodiments, no more than two carbon units of T are optionally replaced by -CO-, -CS-, -B (OH) -, or -B (O (C _1-6 alkyl) -.

, -C(페닐)₂-, -B(OH)-, 및 -CH(OEt)-로 이루어진 그룹으로부터 선택된다. 일부 양태에서는, T는 -CH₂-, -CF₂-, -C(CH₃)₂-,

또는 -C(페닐)₂-이다. 다른 양태에서는, T is -CH₂H₂-, -C(O)-, -B(OH)-, 및 -CH(OEt)-이다. 몇 가지 양태에서, T는 -CH₂-, -CF₂-, -C(CH₃)₂-,

이다. 보다 바람직하게는, T는 -CH₂-, -CF₂-, 또는 -C(CH₃)₂-이다. 몇 가지 양태에서, T는 -CH₂-이다. 또는, T는 -CF₂-이다. 또는, T는 -C(CH₃)₂-이다.In some embodiments, T is _{-CH 2 -, -CH 2 CH 2} -, -CF 2 -, -C (CH 3) 2 -, -C (O) -,

, -C (phenyl) _2- , -B (OH) -, and -CH (OEt) -. In some embodiments, T is _{-CH 2 -, -CF 2 -,} -C (CH 3) 2 -,

Or -C (phenyl) ₂ -. In another _{embodiment, T is -CH 2 H 2 -} , -C (O) -, -B (OH) -, and -CH (OEt) - a. In some embodiments, T is _{-CH 2 -, -CF 2 -,} -C (CH 3) 2 -,

to be. More preferably, T is -CH ₂ -, -CF ₂ -, or -C (CH ₃ ) ₂ -. In some embodiments, T is -CH ₂ - is. Or T is -CF ₂ -. Or, T is -C (CH _{3) 2} - a.

In some embodiments, R ₁ 'and R ₁ "are each independently hydrogen. In some embodiments, R ₁ ' and R ₁ " are each independently -Z ^A R ₅ wherein Z ^A is independently a bond or an optionally substituted A branched or linear C _{1 -6} aliphatic chain, and two or fewer carbon units of Z ^A are optionally and independently selected from -CO-, -CS-, -CONR ^A -, -CONR ^A NR ^A -, -CO ₂ - -OCO-, -NR ^A CO ₂ -, -O-, -NR ^A CONR ^A -, -OCONR ^A -, -NR ^A NR ^A -, -NR ^A CO-, -S-, -SO-, -SO ₂ -, -NR ^a - is replaced by ^{_{a] -, -SO 2 NR a -}} , -NR a SO 2 -, or -NR ^a SO ₂ NR ^a. R ₅ is independently R ^A , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ , or -OCF ₃ . R ^A are each independently C _{1 -8} aliphatic group, an alicyclic, clothing possession hwanjok, aryl, and an optionally substituted group selected from heteroaryl.

In certain embodiments, R ₁ 'is H, C _{1 -6} aliphatic, _{halo, CF 3, CHF 2, -O} (C 1 -6 aliphatic), C ₄ containing a C3-C5 cycloalkyl, or one oxygen atom It is selected from the group consisting of -C ₆ heterocycloalkyl. In certain embodiments, R ₁ 'is H, methyl, ethyl, i - propyl, t - _{butyl, F, Cl, CF 3,} CHF 2, -OCH 3, -OCH 2 CH 3, -O- (i - propyl) And -O- ( t -butyl). More preferably, R ₁ 'is H. Or R ₁ 'is methyl. Or ethyl. Or a CF _3.

In certain embodiments, R ₁ "is selected from the group consisting of H, C _{1 -6} aliphatic, halo, CF _3, CHF _2, and -O (C _{1 -6} aliphatic). In certain embodiments, R _1" is H , methyl, ethyl, i - propyl, t - _{butyl, F, Cl, CF 3,} CHF 2, -OCH 3, -OCH 2 CH 3, -O- (i - propyl) and -O- (t - butyl) ≪ / RTI > More preferably, R ₁ "is H. Or R ₁ " is methyl. Or ethyl. Or a CF _3.

And In certain embodiments, R ^D1 is a 3 "or 4" is bonded to a carbon, -Z ^D R ₉ [wherein, Z ^D are each independently a bond or an optionally branched or linear C _{1 -6} aliphatic chain substituted, Z ^D two carbon units of less than or of the optionally independently ^{-CO-, -CS-, -CONR E -,} -CONR E NR E -, -CO 2 -, -OCO-, -NR E CO 2 -, -O- , -NR ^E CONR ^E -, -OCONR ^E -, -NR ^E NR ^E -, -NR ^E CO-, -S-, -SO-, -SO ₂ -, -NR ^E -, -SO ₂ NR ^E - , -NR ^E SO ₂ -, or -NR ^E SO ₂ NR ^E -. In certain embodiments, Z ^D are independently a bond or an optionally branched or linear C _{1 -6} aliphatic chain substituted, one carbon unit of Z ^D is _{-CO-, -SO-, -SO 2 -,} -COO- , -OCO-, -CONR ^E- , -NR ^E CO-, NR ^E CO ₂ -, -O-, -NR ^E SO ₂ -, or -SO ₂ NR ^E -. In some embodiments, one carbon unit of Z ^D is optionally replaced by -CO-. Or is optionally replaced by -SO-. Or -SO ₂ -. Or -COO-. Or -OCO-. Or -CONR ^E -. Or -NR ^E CO-. Or -NR ^E CO ₂ -. Or is optionally replaced by -O-. Or -NR ^E SO ₂ -. Or -SO ₂ NR ^E -.

In some embodiments, R ₉ is hydrogen, _{halo, -OH, -NH 2, -CN,} -CF 3, -OCF 3, or C _{1 -6} aliphatic, C _{3 -8} cycloaliphatic, 3-8 restore possession hwanjok, a C _{6 -10} aryl, and a 5-10 membered heteroaryl group optionally substituted selected from a group consisting of. In some examples, R ₉ is hydrogen, F, Cl, -OH, -CN, -CF ₃ , or -OCF ₃ . In some embodiments, R ⁹ is C _{1 -6} aliphatic, C _{3 -8} cycloaliphatic, 3-8 restore possession hwanjok, C _{6 -10} aryl, and 5-10 membered heteroaryl [each of R ^E, oxo, Optionally substituted by one or two substituents independently selected from the group consisting of halo, -OH, -NR ^E R ^E , -OR ^E , -COOR ^E , and -CONR ^E R ^E. In some examples, R ₉ is selected from the group consisting of oxo, F, Cl, methyl, ethyl, i -propyl, t -butyl, -CH ₂ OH, -CH ₂ CH ₂ OH, -C (O) _{NH 2, -CH 2 O (C} 1-6 _{alkyl), -CH 2 CH 2 O (} C 1 -6 alkyl), and -C (O) independently selected from the group consisting of (C _{1 -6} alkyl) or 1 Lt; / RTI > is optionally substituted by two substituents.

In one embodiment, R ₉ is hydrogen. In some embodiments, R ₉ is C _{1 -6} straight or branched chain alkyl or C _{2 -6} straight or branched chain group consisting of alkenyl; wherein the alkyl or alkenyl is R ^E, oxo, halo, -OH, -NR ^E R ^E , -OR ^E , -COOR ^E , and -CONR ^E R ^E.

In another embodiment, R ₉ is selected from the group consisting of R ^E , oxo, halo, -OH, -NR ^E R ^E , -OR ^E , -COOR ^E , and -CONR ^E R ^E in one or two substituents independently selected from the group consisting of is a C _{3 -8} cycloaliphatic optionally substituted. Examples of alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

를 포함한다.In another embodiment, R < ₉ > is a 3-8 membered heterocyclic group having 1 or 2 heteroatoms independently selected from the group consisting of O, NH, NR ^E, and S wherein the heterocyclic is R ^E , , -OH, -NR ^E R ^E , -OR ^E , -COOR ^E , and -CONR ^E R ^E groups. 3-8 membered heterocyclic are not intended to be limited to these,

.

를 포함한다.In some other embodiments, R ₉ is an optionally substituted 5-8 membered heteroaryl having 1 or 2 ring atoms independently selected from the group consisting of O, S, and NR ^E. Examples of 5-8 membered heteroaryl include, but are not limited to,

.

In some embodiments, R ^D1 and R ^D2 , together with the carbon to which they are attached, form an optionally substituted 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-2 ring atoms independently selected from the group consisting of O, NH, NR ^E, and S, Form a partially unsaturated or aromatic ring.

을 포함한다.Examples of R ^D1 and R ^D2 formed with a phenyl containing 3 "and 4" carbon atoms include, but are not limited to,

.

In certain embodiments, R ^D2 is H, R ^E, _{halo, -OH, - (CH 2)} r NR E R E, - (CH 2) r -OR E, -SO 2 -R E, -NR E -SO _{^{2 -R E, -SO 2 NR E}} R E, -C (O) R E, -C (O) OR E, -OC (O) OR E, -NR E C (O) OR E , and -C ( O) NR ^E R ^E , wherein r is 0, 1 or 2. In another aspect, R ^D2 is H, C _{1 -6} aliphatic, _{halo, -CN, -NH 2, -NH (} C 1 -6 aliphatic), -N (C _{1 -6} aliphatic) _2, -CH ₂ -N (C _{1-6 aliphatic) 2, -CH 2 -NH (C} 1 -6 _{aliphatic), -CH 2 NH 2, -OH} , -O (C 1 -6 _{aliphatic), -CH 2 OH, -CH 2} - O (C _1-6 aliphatic), -SO ₂ (C _{1 -6} aliphatic), -N (C _{1 -6} aliphatic) -SO ₂ (C _{1 -6 aliphatic), -NH-SO 2 (C} 1 -6 _{aliphatic), -SO 2 NH 2, -SO} 2 NH (C 1 -6 _{aliphatic), -SO 2 N (C 1} -6 _{aliphatic) 2, -C (O) (} C 1 -6 aliphatic), -C ( O) O (C _1-6 aliphatic), -C (O) OH, -OC (O) O (C 1-6 aliphatic), -NHC (O) (C 1 -6 aliphatic), -NHC (O) O (C _1-6 aliphatic), -N (C _{1 -6} aliphatic) C (O) O (C 1 -6 _{aliphatic), -C (O) NH 2} , and -C (O) N (C _{1- 6} aliphatic) ₂ . In some examples, R ^D2 is H, C _{1 -6} aliphatic, _{halo, -CN, -NH 2, -CH 2} NH 2, -OH, -O (C 1 -6 aliphatic), -CH ₂ OH, - SO ₂ (C _{1 -6 aliphatic), -NH-SO 2 (C} 1-6 aliphatic), -C (O) O ( C 1-6 aliphatic), -C (O) OH, -NHC (O) ( C _{1 -6} aliphatic), -C (O) is selected from _{NH 2, -C (O) NH} (C 1-6 aliphatic), and -C (O) N (C _1-6 aliphatic) _2, the group consisting of . For example, R ^D2 can be H, methyl, ethyl, n-propyl, i-propyl, t-butyl, F, Cl, CN, -NH ₂ , -CH ₂ NH ₂ , -OH, -OCH ₃ , -O -ethyl, -O- (i- propyl), -O- (n- _{propyl), -CH 2 OH, -SO 2} CH 3, -NH-SO 2 CH 3, -C (O) OCH 3, -C (O) OCH is selected from _{2 CH 3, -C (O)} OH, -NHC (O) CH 3, -C (O) NH 2, and _{-C (O) N (CH 3} ) group consisting of _2. In one embodiment, R ^D2 is hydrogen. In another embodiment, R ^D2 is methyl. Or R ^D2 is ethyl. Alternatively, R ^D2 is F. Or R ^D2 is Cl. Or a -OCH _3.

In one embodiment, the invention provides compounds of formula VIaa or VIab.

VIaa

VIab

In the above formulas VIaa and VIab,

T, R ^D1 , R ^D2 and R ₁ 'are as defined above.

In one embodiment, T is -CH ₂ -, -CF ₂ -, or -C (CH _{3) 2} - a.

In one embodiment, R ₁ 'is selected from the group consisting of H, C _{1 -6} aliphatic, halo, CF ₃ , CHF ₂ , -O (C _{1 -6} aliphatic), C ₃ -C ₅ cycloalkyl, ≪ RTI ID = 0.0 > C ₄ -C ₆ < / RTI > heterocycloalkyl. An exemplary embodiment is selected from H, methyl, ethyl, i - propyl, t - _{butyl, F, Cl, CF 3,} CHF 2, -OCH 3, -OCH 2 CH 3, -O- (i - propyl), -O- ( t -butyl), cyclopropyl, or oxetanyl. More preferably, R ₁ 'is H. Or R ₁ 'is methyl. Or ethyl. Or a CF _3. Or oxetanyl.

In one embodiment, R ^D1 is Z ^D R ₉ [wherein, Z ^D is _{CONH, NHCO, SO 2 NH,} SO 2 N (C 1 -6 _{alkyl), NHSO 2, CH 2 NHSO} 2, CH 2 N (CH ₃ ) SO ₂ , CH ₂ NHCO, COO, SO ₂ , or CO. In one embodiment, R ^D1 is Z ^D R ₉ [wherein, Z ^D is _{CONH, SO 2 NH, SO 2} N (C 1 -6 _{alkyl), CH 2 NHSO 2, CH} 2 N (CH 3) SO 2, CH ₂ NHCO, COO, SO ₂ , or CO.

In one embodiment, Z ^D is COO and R ₉ is H. In one embodiment, Z ^D is COO and R ₉ is an optionally substituted straight or branched C _{1 -6} aliphatic. In one embodiment, Z ^D is COO and R ₉ is optionally substituted straight or branched C _{1 -6} alkyl. In one embodiment, Z ^D is COO and R ₉ is C _{1 -6} alkyl. In one embodiment, Z ^D is COO and R ₉ is methyl.

In one embodiment, Z ^D is CONH and R ₉ is H. In one embodiment, Z ^D is CONH and R ₉ is an optionally substituted straight or branched C _{1 -6} aliphatic. In one embodiment, Z ^D is CONH and R ₉ is straight or branched C _{1 -6} alkyl. In one embodiment, Z ^D is CONH and R ₉ is methyl. In one embodiment, Z ^D is CONH and R ₉ is optionally substituted straight or branched C _{1 -6} alkyl. In one embodiment, Z ^D is CONH and R ₉ is 2- (dimethylamino) -ethyl.

In some embodiments, Z ^D is CH ₂ NHCO and R ₉ is an optionally substituted straight or branched C _{1 -6} aliphatic or optionally substituted alkoxy. In certain embodiments, Z ^D is CH ₂ NHCO and, R ₉ is halo, oxo, hydroxyl a chamber optionally substituted straight or branched C _{1 -6} alkyl, or an aliphatic, cyclic, aryl, heteroaryl, alkoxy, amino, carboxyl , Or carbonyl. In one embodiment, Z ^D is CH ₂ NHCO and R ₉ is methyl. In one embodiment, Z ^D is CH ₂ NHCO and R ₉ is CF ₃ . In one embodiment, Z ^D is CH ₂ NHCO and R ₉ is t-butoxy.

In one embodiment, Z ^D is SO ₂ NH and R ₉ is H. In some embodiments, Z ^D is SO ₂ NH and R ₉ is an optionally substituted straight or branched C _{1 -6} aliphatic. In some embodiments, Z ^D is SO ₂ NH and R ₉ is straight or branched C _{1 -6} alkyl, optionally substituted with halo, oxo, hydroxyl, or C _{1 -6} aliphatic, 3-8 membered cyclic, C _{6 -10} aryl, 5-8 membered heteroaryl, alkoxy, amino, amido, carboxyl and carbonyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is methyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is ethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is i -propyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is t -butyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 3,3-dimethylbutyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH ₃ ) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH (CH ₃ ) OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH ₂ OH) ₂ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH (OH) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH (OH) CH ₂ CH ₃ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is C (CH ₃ ) ₂ CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH ₂ CH ₃ ) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH ₂ OCH ₂ CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is C (CH ₃ ) (CH ₂ OH) ₂ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH (OH) CH ₂ C (O) OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH ₂ N (CH ₃ ) ₂ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH ₂ CH ₂ NHC (O) CH ₃ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH (CH ₃ ) ₂ ) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is CH (CH ₂ CH ₂ CH ₃ ) CH ₂ OH. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 1-tetrahydrofuryl-methyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is furylmethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is (5-methylfuryl) -methyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2-pyrrolidinylethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2- (1-methylpyrrolidinyl) -ethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2- (4-morpholinyl) -ethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 3- (4-morpholinyl) -propyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is C (CH ₂ CH ₃ ) (CH ₂ OH) ₂ . In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2- (1 H -imidazol-4-yl) ethyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 3- (1 H -imidazol-1-yl) -propyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is 2- (2-pyridinyl) -ethyl.

In certain embodiments, Z ^D is SO ₂ NH, R ₉ is a C _{1 -6} aliphatic group optionally substituted. In some examples, Z ^D is SO ₂ NH, R ₉ is optionally substituted C _{1 -6} cycloalkyl. In some instances, Z ^D is SO ₂ NH and R ₉ is C _{1 -6} cycloalkyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is cyclobutyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is cyclopentyl. In one embodiment, Z ^D is SO ₂ NH and R ₉ is cyclohexyl.

In some embodiments, Z ^D is SO ₂ N (C _{1 -6} alkyl) and R ₉ is an optionally substituted straight or branched C _{1 -6} aliphatic or optionally substituted alicyclic. In some embodiments, Z ^D is SO ₂ N (C _{1 -6} alkyl) and R ₉ is an optionally substituted straight or branched C _{1 -6} aliphatic. In some embodiments, Z ^D is SO ₂ N (C _{1 -6} alkyl) and R ₉ is optionally substituted straight or branched C _{1 -6} alkyl or optionally substituted straight or branched C _{1 -6} alkenyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is methyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is n-propyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is n-butyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is cyclohexyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is allyl. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is CH ₂ CH ₂ OH. In one embodiment, Z ^D is SO ₂ N (CH ₃ ) and R ₉ is CH ₂ CH (OH) CH ₂ OH. In one embodiment, Z ^D is SO ₂ N (CH ₂ CH ₂ CH ₃ ) and R ₉ is cyclopropylmethyl.

In one embodiment, Z ^D is CH ₂ NHSO ₂ and R ₉ is methyl. In one embodiment, Z ^D is CH ₂ N (CH ₃ ) SO ₂ and R ₉ is methyl.

을 포함한다.In certain embodiments, Z is ^D is SO _2, R ₉ is optionally substituted C _{1 -6} linear or branched aliphatic or nitrogen, oxygen, sulfur, one, two or three ring members selected from the group consisting of SO ₂ and SO Lt; / RTI > is an optionally substituted 3-8 membered heterocyclic. In some embodiments, Z ^D is SO ₂ and R ₉ is linear or branched C _{1 -6} alkyl or a 3-8 membered heterocyclic ring optionally substituted with 1, 2, or 3 oxo, halo, _{1 -6} aliphatic, carbonyl, amino, and carboxy. In one embodiment, Z ^D is SO ₂ and R ₉ is methyl. In some embodiments, Z ^D is SO ₂ , An example of R ₉ is

.

In some embodiments, R ^D2 is H, hydroxyl, halo, C _{1 -6} alkyl, C _{1 -6} alkoxy, C _{3 -6} cycloalkyl, or NH ₂ . In some examples, R ^D2 is H, halo, C _{1 -4} alkyl or C _{1 -4} alkoxy. Examples of R ^D2 include H, F, Cl, methyl, ethyl, and methoxy.

In certain embodiments, the present invention provides a compound of formula Iaa or Iab, or a pharmaceutically acceptable salt thereof.

≪ RTI ID =

Iab

In the above formulas Iaa and Iab,

R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ and n are as defined above.

In some embodiments, R < _{1 >} is optionally substituted aryl. In some examples, R ₁ is 1, 2, or 3 halo, OH, -O (C _{1 -6} aliphatic), amino, C _{1 -6} aliphatic, C _{3 -7} cycloaliphatic, 3-8 restore possession a hwanjok, C _{6 -10} aryl, or 5-8 membered heteroaryl optionally substituted by phenyl. In some embodiments, R < ₁ > is phenyl optionally substituted with alkoxy, halo, or amino. In one embodiment, R < ₁ > is phenyl. In one embodiment, R < ₁ > is phenyl substituted by Cl, methoxy, ethoxy, or dimethylamino.

In some embodiments, R ₂ is hydrogen. In some embodiments, R ₂ is an optionally substituted C _{1 -6} aliphatic.

In some aspects, R _3, R _'3, and to which they are attached carbon atom to form an optionally substituted C _{3 -8} cycloaliphatic, or an optionally substituted 3-8 restore possession hwanjok. In some aspects, R _3, R _'3 and who they are carbon atoms bonded to form an optionally substituted C _{3 -8} cycloalkyl. In one example, R ₃ , R ' ₃ and the carbon atom to which they are attached are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted. In one example, R ₃ , R ' ₃ and the carbon atom to which they are attached is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some instances, R ₃ , R ' ₃ and the carbon atom to which they are attached is cyclopropyl.

(여기서, T는 위에서 정의한 바와 같다)이다. 몇 가지 예에서, T는 -CH₂-이다.In some embodiments, R < ₄ > is optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, R < ₄ > is optionally substituted phenyl. In some embodiments, R < ₄ > is phenyl fused with a 3, 4, 5 or 6 membered heterocyclic having 1, 2 or 3 rings selected from oxygen, sulfur and nitrogen. In some embodiments, R < ₄ > is

(Where T is as defined above). In some examples, T is -CH ₂ - is.

Alternative embodiments of R ₁ , R ₂ , R ₃ , R ' ₃ , R ₄ and n in formula Iaa or Iab are as defined for formula I, Ia and embodiments thereof.

Exemplary compounds of the present invention include, but are not limited to, those illustrated in Table 1 below.

Composite scheme

The compounds of the present invention can be prepared in a known manner, or as exemplified in the Examples. In one example where R < _{1 >} is aryl or heteroaryl, compounds of the present invention may be prepared as described in Scheme I.

Scheme I

a) 50% NaOH, XR ₃ -R ' ₃ -Y, BTEAC; X, Y = leaving group; b) SOCl _2, DMF; c) pyridine; d) R ₁ -B (OR) ₂ , Pd (dppf) Cl ₂ , K ₂ CO ₃ , DMF, H ₂ O

Reaction Scheme II

_{a) Pd (PPh 3) 4} , CO, MeOH; b) LiAlH ₄ , THF; c) SOCl ₂ ; d) NaCN; e) NBS or NCS, AIBN, CX ₄ (X = Br or Cl)

Scheme III

a) pyridine, DCM; b) R ₁ -B (OR) ₂ , Pd (dppf) Cl ₂ , K ₂ CO ₃ , DMF, H ₂ O

Scheme IV

a) pyridine, DCM; b) R ₁ -B (OR) ₂ , Pd (dppf) Cl ₂ , K ₂ CO ₃ , DMF, H ₂ O

Referring to Scheme I, the nitrile (i) is dihalo-aliphatically alkylated with a base, such as, for example, 50% sodium hydroxide and optionally in the presence of a base, such as benzyltriethylammonium chloride (BTEAC) To produce the corresponding alkylated nitrile (not shown) which produces acid (ii) upon hydrolysis (step a). Compound (ii) is converted to the acid chloride (iii) with the appropriate agent, for example thionyl chloride / DMF. Reaction of the acid chloride (iii) with aminopyridine (iv) wherein X is halo gives the amide (v) (step c). Amide (v) is reacted with an optionally substituted boronic acid derivative and a catalyst such as palladium acetate or dichloro- [1,1-bis (diphenylphosphino) ferrocene] palladium (II) (Pd (dppf) Cl ₂ ) To provide a compound of the invention wherein R < ₁ > is aryl, heteroaryl or cycloalkenyl (step d). The boronic acid derivative (vi) is commercially available or can be prepared by known methods, such as, for example, the reaction of an aryl bromide with a diborane ester in the presence of a coupling agent such as palladium acetate as described in the examples.

(여기서, X는 할로이고, Q는 C_{1 -6} 지방족, 아릴, 헤테로아릴, 또는 3 내지 10원 지환족 또는 복소지환족이다)과 같은 적합하게 치환된 아미노피리딘을 사용하여 반응식 I의 단계 a, b 및 c에 기재된 바와 같이 제조할 수 있다.
In another example where one R < ₁ > is aryl and the other R < ₁ > is an aliphatic, alkoxy, alicyclic, or heterocyclic alicyclic group, the compounds of the invention may be used as substituents for the aminopyridine (iv)

(I) or a pharmaceutically acceptable salt thereof, using a suitably substituted aminopyridine, such as a compound of formula I, wherein X is halo and Q is a C _{1 -6} aliphatic, aryl, heteroaryl, or a 3-10 membered cycloaliphatic or heterocyclic ring , < / RTI > b and c.

Formulation, administration and use

Pharmaceutically acceptable compositions

Thus, in another aspect of the invention, there is provided a pharmaceutically acceptable composition comprising any of the compounds described herein, optionally including a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the composition optionally additionally comprises one or more additional therapeutic agents.

It will also be appreciated that certain compounds of the present invention may exist in free form for treatment, or where necessary, as a pharmaceutically acceptable derivative or prodrug thereof. In accordance with the present invention, pharmaceutically acceptable derivatives or prodrugs include, but are not limited to, the compounds described herein upon administration to a patient in need thereof, or a medicament that can directly or indirectly provide the metabolite or residue thereof Acceptable salts, esters, salts of such esters, other adducts or derivatives thereof.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, It is the salt corresponding to the profit / risk ratio. A pharmaceutically acceptable salt is any non-toxic salt or ester of a compound of the present invention, which upon administration to a receptor can directly or indirectly provide a compound of the present invention, or an inhibitoryly active metabolite or residue thereof, .

Pharmaceutically acceptable salts are well known in the art. For example, see SM Berge, et < RTI ID = 0.0 > al ., J. Pharmaceutical Sciences , 1977, 66 , 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic, oxalic, maleic, tartaric, Or a salt of an amino group formed with malonic acid, or by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propio Hydroxides, hydroiodides, hydroiodides, hydroiodides, hydroiodides, hydroiodides, hydroiodides, hydroiodides, hydroiodides, hydroxides, hydroxides, Lactate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate Phthalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, Include, pivalate, propionate, stearate, succinate, sulfate, tartrate, such as thiocyanate, p- toluenesulfonate, undecanoate, valerate salts. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ _- include (C _{1 4} alkyl) ₄ salts. The present invention also contemplates quaternization of any basic nitrogen containing group of compounds described herein. Water- or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, if necessary, non-toxic ammonium, ammonium, or ammonium salts formed with counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, Ammonium quaternary ammonium and amine cations.

As described above, the pharmaceutically acceptable compositions of the present invention, as used herein, are intended to include any and all solvents, diluents or other liquid vehicles, dispersions or suspending aids, suitable for the particular dosage form desired, A pharmaceutically acceptable carrier, adjuvant or vehicle, including an active agent, isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant and the like. Remington: The Science and Practice of Pharmacy , 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology , eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference) discloses various carriers used to formulate pharmaceutically acceptable compositions and their preparation Is described. By interacting in a deleterious manner with, for example, any unnecessary biological action, or with any other component (s) of the other pharmaceutically acceptable composition, any conventional carrier medium may be used that is compatible with the compounds of the present invention Except in the case, its use is contemplated to be within the scope of the present invention. Some examples of materials that may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances, For example, it is possible to use a mixture of phosphates, glycine, sorbic acid or potassium sorbate, a partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogenphosphate, sodium chloride, Polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, parent fats, sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Celluloses and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Tragacanth powder; Malt; gelatin; talc; Excipients such as cocoa butter and suppository wax; Oils, for example peanut oil, cottonseed; Safflower oil; Sesame oil; olive oil; Corn oil and soybean oil; Glycols such as propylene glycol or polyethylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Distillation water; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffer solutions as well as non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, emollients, coatings, sweeteners, flavors and fragrances, Preservatives and antioxidants may also be present in the composition, as judged by the formulator.

Use of compounds and pharmaceutically acceptable compositions

In another aspect, the invention provides a method of treating a condition, disease, or disorder associated with ABC transporter activity. In a particular embodiment, the invention provides a composition comprising a compound of formulas I, II, III, IV, Va, Vb, Ia, Iaa and Iab in a subject in need thereof, , A method of treating a condition, disease or disorder associated with a deficiency of ABC transporter activity.

In certain preferred embodiments, the invention provides a method of treating a mammal comprising administering to a mammal a composition comprising an effective amount of a compound of any of formulas I, II, III, IV, Va, Vb, Ia, Iaa and Iab, For example, cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency such as protein C deficiency, type 1 hereditary vascular edema, lipid deficiency disorders such as familial hypercholesterolemia, Polycystic ovarian disease, polycystic ovary syndrome, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, / Hyperinsulinemia, diabetes mellitus, laryngeal dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type 1 glycan degradation CDG, hereditary emphysema, congenital hyperthyroidism, incomplete osteogenesis, Alzheimer's disease, Parkinson ' s disease, Alzheimer ' s disease, Alzheimer ' s disease, Alzheimer ' s disease, Alzheimer ' Such as Huntington's disease, type I spinal cord cerebellar ataxia, vertebral and bulbar muscular dystrophy, dentigerous nucleus proliferative dystrophy, and atrophic dystrophy, and atypical hypersomnia, , As well as spongiform encephalopathy such as hereditary Croufeld-Jacob disease (due to defective prion protein treatment), Fabry's disease, Strasler-Shinkler disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease COPD), dry eye syndrome, and Southe Gren syndrome.

According to a preferred alternative embodiment, the present invention provides a method of treating a mammal comprising administering to a mammal a composition comprising an effective amount of a compound of formula I, II, III, IV, Va, Vb, Ia, Iaa and Iab, A method for treating cystic fibrosis.

An "effective amount" of a compound or pharmaceutically acceptable composition according to the present invention is selected from the group consisting of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency such as protein C deficiency, type 1 hereditary vascular edema, Deficiency, such as, for example, familial hypercholesterolemia, type 1-chylomicronemia, non-beta lipoproteinemia, lysosomal storage diseases such as I-cell disease / hypoglycemia, mucopolysaccharidosis, -Saks, type-II Crigler-Najjar type II, polycystic dyslipidemia / hyperinsulinemia, diabetes mellitus, dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type 1 glycan (DI), neuroblastoma diabetes insipidus, chronic diabetes insipidus, Charko-Maritou syndrome, perizarinosis, diabetic retinopathy, diabetic retinopathy, diabetic retinopathy, degenerative CDG, hereditary emphysema, congenital hyperthyroidism, incomplete osteogenesis, hereditary hypofibrinogenesis, - Huntington's disease, Type I spinal cord cerebellum, cerebral palsy, cerebral palsy, cerebellum, cerebellum, cerebellum, cerebellum, Spinal and bulbar muscular dystrophy, dental nucleus proliferative vertigo nucleus atrophy, and myotonic dystrophies such as spongiform encephalopathy such as hereditary Croufeld-Jacob disease, Fabry disease, Straussler-Shinkler disease, Is an amount effective to treat or alleviate one or more of the following: diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD), dry eye syndrome, and Sjogren's syndrome.

The compounds and compositions according to the methods of the present invention are useful for the treatment and / or prophylaxis of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency, for example, protein C deficiency, type 1 hereditary vascular edema, Hyperlipoproteinemia, hypercholesterolemia, type 1-chylomicronemia, non-beta-lipoproteinemia, lysosomal storage diseases such as I-cell disease / hypoglycemia, mucopolysaccharidosis, Sandhoff / - Najar, multiple endocrine disorders / hyperinsulinemia, diabetes, dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type 1 glycan degradation CDG, hereditary emphysema, congenital hyperthyroidism, incomplete bone formation , Hereditary hypofibrinogenesis, ACT deficiency, diabetes insipidus (DI), neuroblastoma diabetes insipidus, NIDDM, Charcot-Maritou syndrome, Perizaeus-Mertzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's disease, type I spinal cord cerebellar ataxia, spinal and bulbar muscular dystrophy, Chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), diabetic retinopathy, And any dosage regimen effective to treat or alleviate the severity of one or more of the conditions listed above.

The exact amount required depends on the species, age and general condition of the subject, the severity of the infection, the specific agent, the mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and volume uniformity. As used herein, the phrase "dosage unit form" refers to a physically discrete unit of formulation suitable for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined within the scope of safe medical judgment, in the presence of a specialist. The specific effective dose level for any particular patient or organism will depend on the severity of the disorder and disorder being treated; The activity of the specific compound used; The particular composition used; Age, weight, general health, sex and diet of the patient; The time of administration, route of administration and rate of excretion of the particular compound employed; Treatment period; The drug used in combination with or concurrently with the particular compound used, and factors well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal, most preferably a human.

The pharmaceutically acceptable compositions of the present invention may be formulated for oral, rectal, parenteral, buccal, vaginal, intraperitoneal, topical (as powders, ointments or drops), oral , Oral or cost-effective spray, and the like. In certain embodiments, the compounds of the invention are administered orally or parenterally at a dosage level of from about 0.01 to about 50 mg / kg body weight, preferably from about 1 to about 25 mg / kg body weight of the subject once or more than once daily The desired therapeutic effect can be obtained.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms can be formulated with inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl (Especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, Fatty acid esters of furyl alcohol, polyethylene glycol and sorbitan, and mixtures thereof. In addition to inert carriers, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a solution in a sterile injectable solution, suspension or emulsion, for example, 1,3-butanediol in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be used include water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally used as a solvent or suspending medium. For this purpose, blended nonvolatile oils including synthetic mono- or diglycerides may be used. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

The injectable formulations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use have.

To sustain the effect of the compounds of the present invention, it may often be desirable to delay the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished using liquid suspensions of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on the dissolution rate, and the dissolution rate may depend on the crystal size and crystal form. Alternatively, delayed absorption in the form of a parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. The injectable depot forms are prepared by forming microencapsule matrices of compounds in biodegradable polymers, for example, polylactide-polyglycolide. Depending on the ratio of compound to polymer and the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compounds in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably prepared by dissolving the compound of the invention in a suitable non-polar excipient or carrier, for example, cocoa butter, polyethylene glycol or in solid or liquid form at ambient temperature, And a suppository wax releasing the compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be admixed with one or more inert pharmaceutically acceptable excipients or carriers, for example sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starch, lactose, sucrose, C) humectants such as glycerol, d) disintegrating agents, such as glucose, mannitol and silicic acid, b) binders, for example carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, E) a solution retarder such as paraffin, f) an absorption promoter such as a quaternary ammonium compound, g) an antioxidant, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific silicates and sodium carbonate, Wetting agents such as cetyl alcohol and glycerol monostearate h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, Magnesium, solid polyethylene glycols, sodium lauryl and la are mixed sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer.

In addition, similar types of solid compositions can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, tablets, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Optionally, it may contain opacifying agents and may also be in the form of a composition which uniquely or preferentially releases the active ingredient (s) in a delayed manner, optionally to a particular part of the intestinal tract. Examples of implant compositions that can be used include polymeric materials and waxes. In addition, similar types of solid compositions can be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

In addition, the active compound may be microencapsulated with one or more of the aforementioned excipients. Solid dosage forms of tablets, tablets, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release modifying coatings and other coatings well known in the pharmaceutical formulating arts. In such solid dosage forms, the active compound may be mixed with one or more inert diluents, e. G. Sucrose, lactose or starch. In addition, such dosage forms may comprise, in the usual practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer. They may optionally contain opacifying agents and may also be in the form of a composition which uniquely or preferentially releases the active ingredient (s) in a delayed manner, in particular parts of the intestinal tract. Examples of implant compositions that can be used include polymeric materials and waxes.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active compound is mixed with a pharmaceutically acceptable carrier under sterile conditions, and any preservatives or buffers may be required. In addition, ophthalmic formulations, ear mucus and mucous membranes are considered to fall within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches with the added benefit of regulating delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispensing the compounds in suitable media. In addition, absorption promoters can be used to increase the flow rate of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the present invention are useful as modulators of ABC transporters. Thus, while not wishing to be bound by any particular theory, compounds and compositions are particularly useful for treating or ameliorating the hyperactivity or inactivity of an ABC transporter relative to the severity of the disease, condition, or disorder associated with the disease, condition, or disorder. A disease, condition or disorder may also be referred to as "ABC transporter mediated disease, condition or disorder" when the hyperactivity or inactivity of the ABC transporter is associated with a particular disease, condition or disorder. Thus, in another aspect, the invention provides a method of treating or ameliorating the severity of a disease, condition, or disorder in which the hyperactivity or inactivity of the ABC transporter is associated with the disease state.

The activity of the compounds used in the present invention as modulators of ABC transporters can be assayed according to the methods generally described in the art and described in the Examples below.

It is also to be understood that the compounds of the present invention and pharmaceutically acceptable compositions can be used in combination therapy, i.e., the compounds and the pharmaceutically acceptable compositions are administered concurrently with one or more other desired therapeutic agents or medical procedures, It will be understood that the compounds of the invention may be administered after administration. The specific combination of therapies (therapeutic agents or procedures) for use in combination therapy contemplates the harmonization of the desired therapeutic agent and / or procedure with the therapeutic effect to be achieved. It is also to be understood that the treatment employed may achieve the desired effect on the same disorder (e. G., The compound of the present invention may be administered concurrently with another agent used to treat the same disorder) E. G., Modulation of side effects). ≪ / RTI > As used herein, additional therapeutic agents conventionally administered to treat or prevent a particular disease or condition are known as "suitable for the disease or condition being treated ".

The amount of the additional therapeutic agent present in the composition of the present invention is not greater than the amount conventionally administered in a composition comprising such therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the composition will range from about 50 to 100% of the amount normally present in the composition comprising the additional therapeutic agent as the sole therapeutically active agent.

The compounds of the present invention or pharmaceutically acceptable compositions thereof may be incorporated into a medical device for implantation, for example, a composition for prosthetic, artificial valve, vascular graft, stent and catheterization. Accordingly, in another aspect, the invention includes a composition for coating a device for implantation comprising a compound of the invention as described above and a carrier suitable for coating the implantable device. In another aspect, the invention includes a device for implantation coated with a composition comprising a compound of the invention as described above, and a carrier suitable for coating the device for implantation. Suitable coatings and general manufacturing methods of coated implants are described in U.S. Pat. Patent No. 6,099,562; 5,886, 026; And 5,304,121. The paints are typically biocompatible polymeric materials, such as hydrogel polymers, polymethylsidysiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be additionally covered by a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipids, or combinations thereof to impart controlled release properties to the composition.

Another aspect of the present invention is the use of a compound of formula I or a composition comprising said compound for the manufacture of a medicament for the treatment of a biological sample or an ABC transporter of a patient (e.g., in vitro or in vivo) Lt; / RTI > activity. The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; A biopsy material obtained from a mammal or an extract thereof; And blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

Adjustment of ABC transporter activity in biological samples is useful for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, studies of ABC transporters in biological and pathological phenomena and comparative evaluation of novel modulators for ABC transporters.

In another embodiment, there is provided a method of modulating the activity of an anion channel in vitro or in vivo, comprising contacting an anion channel with a compound of formula I, II, III, IV, Va, Vb, Ia, Iaa and Iab / RTI > In a preferred embodiment, the anion channel is a chloride channel or a bicarbonate channel. In another preferred embodiment, the anion channel is a chloride channel.

According to an alternative embodiment, the invention provides a method of treating a cell, comprising contacting a cell in need of an increase in the number of functional ABC transporters with a compound of formula I, II, III, IV, Va, Vb, Ia, Lt; RTI ID = 0.0 > ABC < / RTI > The term "functional ABC transporter" as used herein means an ABC transporter capable of transporting activity. In a preferred embodiment, the functional ABC transporter is CFTR.

In another preferred embodiment, the activity of the ABC transporter is determined by measuring the transverse membrane voltage potential. Means for measuring the voltage potential across the membrane in a biological sample may be by methods known in the art, such as using optical film potential assays or other electrophysiological methods.

Optical film potential assays are used to measure fluorescence changes such as voltage / iron probe readers (VIPR) (Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439, Gonzalez, JE and RY Tsien energy transfer in single cells "Biophys J 69 (4): 1272-80; The voltage sensitive FRET sensor described in Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that uses fluorescence resonance energy transfer" Chem Biol 4 (4): 269-77 is used.

This voltage sensitive assay is based on changes in fluorescence resonance energy transfer (FRET) between the membrane-soluble, voltage sensitive dye DiSBAC ₂ (3) and the fluorescent phospholipid CC2-DMPE (attached to the outer leaflet of the plasma membrane and acting as an FTET donor) . The change in membrane potential (V _m ) redistributes the negatively charged DiSBAC ₂ (3) across the plasma membrane and changes the amount of energy transfer from CC2-DMPE. Changes in fluorescence emission can be monitored using an integrated liquid handler and a fluorescence detector, VIPR ^TM II, designed to perform cell-based screens on 96-well or 384-well microtiter plates.

(I) comprising a compound of any one of the above embodiments, and a) contacting the composition with a biological sample, wherein the composition comprises a compound of Formula I, II, III, IV, Va, Vb, Ia, Iaa and Iab, (B) a kit for use in measuring the activity of an ABC transporter or fragment thereof in a biological sample in vitro or in vivo, comprising instructions (ii) for measuring the activity of the ABC transporter or fragment thereof Lt; / RTI > In one embodiment, the kit comprises a) contacting an additional composition with a biological sample, b) measuring the activity of the ABC transporter or fragment thereof in the presence of the additional compound, c) determining the activity of the ABC transporter To the density of the ABC transporter in the presence of the composition of the compounds of formulas I, II, III, IV, Va, Vb, Ia, Iaa and Iab. In a preferred embodiment, the kit is used to measure the density of the CFTR.

The present invention provides a method for preparing a novel compound which can act as an ATP-binding cassette (ABC) transporter. The compounds produced by the present invention can be used to treat or alleviate hereditary emphysema, chronic obstructive pulmonary disease (COPD) or ocular dryness.

Manufacturing and Example

General Process I: Carboxylic acid  Configuration block

Benzyltriethylammonium chloride (0.025 eq.) And the appropriate dihalo compound (2.5 eq.) Were added to the substituted phenylacetonitrile. The mixture was heated at 70 < 0 > C and then 50% sodium hydroxide (10 eq) was slowly added to the mixture. The reaction was stirred at 70 < 0 > C for 12-24 hours to fully form the cycloalkyl moiety and then heated at 130 < 0 > C for 24-48 h to convert completely from the nitrile to the carboxylic acid. The dark brown / black reaction mixture was diluted with water, extracted three times each with ethyl acetate and then dichloromethane to remove byproducts. The basic aqueous solution was acidified to less than pH 1 with concentrated hydrochloric acid and the precipitate that started to form at pH 4 was filtered and washed twice with 1 M hydrochloric acid. The solid material was dissolved in dichloromethane and extracted twice with 1 M hydrochloric acid and once with a saturated aqueous solution of sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness to yield the cycloalkylcarboxylic acid.

A. 1- Benzo [1,3] dioxol -5-yl- cyclopropanecarboxylic acid

1-bromo-2-chloro-ethane (9.00 ml, 109 mmol) and benzyltriethylammonium chloride (0.181 g, 0.795 mmol) Was heated at 70 < 0 > C and 50% (wt./wt.) Aqueous sodium hydroxide (26 ml) was slowly added to the mixture. The reaction was stirred at 70 < 0 > C for 18 h and then heated at 130 < 0 > C for 24 h. The dark brown reaction mixture was diluted with water (400 mL) and extracted once with the same volume of ethyl acetate and once with the same volume of dichloromethane. The basic aqueous solution was acidified to less than pH 1 with concentrated hydrochloric acid, and the precipitate was filtered and washed with 1 M hydrochloric acid. The solid was dissolved in dichloromethane (400 mL) and extracted twice with the same volume of 1 M hydrochloric acid, once with a saturated aqueous solution of sodium chloride. The organic solution was dried over sodium sulfate and evaporated to dryness to give a white to slightly off-white solid (5.23 g, 80%). ESI-MS m / z Calcd: 206.1, found: 207.1 (M + l) ⁺ . Retention time 2.37 minutes. ^{1 H NMR (400 MHz, DMSO} -d 6) δ 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79 (m, 2H), 6.88 (m, 1H ), 12.26 (s, 1 H).

General process II : Carboxylic acid  Configuration block

Sodium hydroxide (50% aqueous solution, 7.4 eq.) Was slowly added to a mixture of suitable phenylacetonitrile, benzyltriethylammonium chloride (1.1 eq) and a suitable dihalo compound (2.3 eq) at 70 < 0 > C. The mixture was stirred overnight at 70 [deg.] C and the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to give crude cyclopropanecarbonitrile, which was used directly in the next step.

The crude cyclopropanecarbonitrile was heated at reflux for 2.5 hours in 10% aqueous sodium hydroxide (7.4 eq). The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give the cyclopropanecarboxylic acid as a white solid.

General process III : Carboxylic acid  Configuration block

B. 1- (2,2 -Difluoro - benzo [1,3] dioxol -5-yl) -cyclopropanecarboxylic acid

Step a: 2,2-Difluoro-benzo [1,3] dioxole-5-carboxylic acid methyl ester

To a solution of 5-bromo-2,2-difluoro-benzo [1,3] dioxole (11.8 g, 50.0 mmol) in methanol (20 ml) containing acetonitrile (30 ml) and triethylamine ) and tetrakis (triphenylphosphine) palladium (0) and a solution of _{[Pd (PPh 3) 4,} 5.78g, 5.00mmol] was stirred under a carbon monoxide atmosphere at 75 ℃ (55PSI), 15 hours (oil bath temperature). The cooled reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography to give crude 2,2-difluoro-benzo [1,3] dioxole-5-carboxylic acid methyl ester (11.5 g) which was used directly in the next step.

Step b: (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -methanol

To a stirred solution of crude 2,2-difluoro-benzo [1,3] dioxole-5-carboxylic acid methyl ester (11.5 g) in 20 mL anhydrous tetrahydrofuran (THF) Was slowly added to a suspension of lithium aluminum hydride (4.10 g, 106 mmol). The mixture was then allowed to warm to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0 C and treated with water (4.1 g) followed by sodium hydroxide (10% aqueous solution, 4.1 ml). The resulting slurry was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by silica gel column chromatography to give (2,2-difluoro-benzo [1,3] dioxol-5-yl) -methanol (7.2 g, 38 mmol, 76%) as a colorless oil.

Step c: 5-Chloromethyl-2,2-difluoro-benzo [1,3] dioxole

(45 g, 38 mmol) was added to a solution of (2,2-difluoro-benzo [1,3] dioxol-5-yl) -methanol (7.2 g, 38 mmol) in dichloromethane Was slowly added to the solution. The resulting mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was partitioned between an aqueous solution of saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL). The separated aqueous layer was extracted with dichloromethane (150 ml) and the organic layer was dried over sodium sulfate, filtered and evaporated to dryness to give crude 5-chloromethyl-2,2-difluoro-benzo [ ] Dioxole (4.4 g), which was used directly in the next step.

Step d: (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -acetonitrile

A mixture of crude 5-chloromethyl-2,2-difluoro-benzo [1,3] dioxole (4.4 g) and sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 ml) And stirred overnight. The reaction mixture was poured into ice and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and evaporated to dryness to give crude (2,2-difluoro-benzo [1,3] dioxol-5-yl) -acetonitrile .

Step e: 1- (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile

Sodium hydroxide (50% aqueous solution, 10 ml) was added to a stirred solution of crude (2,2-difluoro-benzo [1,3] dioxol-5-yl) -acetonitrile, benzyltriethylammonium chloride 15.3 mmol) and 1-bromo-2-chloroethane (4.9 g, 38 mmol). The mixture was stirred at 70 < 0 > C overnight, then the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness to give crude 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarbonitrile Was used directly in the step.

Step f: l- (2,2-Difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid

(Crude compound from the last step) was dissolved in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours < RTI ID = 0.0 >Lt; / RTI > The cooled reaction mixture was washed with ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1- (2,2-difluoro-benzo [1,3] dioxol-5-yl) -cyclopropanecarboxylic acid as a white solid (0.15 g, 1.6% over four steps) Respectively. ESI-MS m / z calc 242.2, found 243.3 (M + l) ⁺ ; ¹ H NMR (CDCl ₃ )? 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H).

C. 2- (4 -Chloro- 3 -methoxyphenyl ) acetonitrile

Step a: 1-Chloro-2-methoxy-4-methyl-benzene

To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH ₃ CN (700 mL) was added CH ₃ I (111 g, 0.78 mol) and K ₂ CO ₃ (180 g, 1.3 mol). The mixture was stirred at 25 < 0 > C overnight. The solid was filtered and the filtrate was evaporated in vacuo to give l-chloro-2-methoxy-4-methyl-benzene (90 g, 89%). ¹ H NMR (300 MHz, CDCl ₃ )? 7.22 (d, J = 7.8 Hz, 1H), 6.74-6.69 (m, 2H), 3.88 (s, 3H), 2.33 (s, 3H).

Step b: 4-Bromomethyl-l-chloro-2-methoxy-benzene

It was added benzene NBS (57.2g, 0.32mol) and AIBN (10g, 60mmol) to a solution of _{(50g, 0.32mol) - CCl 4} (350㎖) 1- chloro-2-methoxy-4-methyl-of. The mixture was heated to reflux for 3 hours. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether / EtOAc = 20: 1) to give 4-bromomethyl-1-chloro-2-methoxy- benzene (69 g, 92% . ¹ H NMR (400 MHz, CDCl ₃ )? 7.33-7.31 (m, 1H), 6.95-6.91 (m, 2H), 4.46 (s, 2H), 3.92 (s, 3H).

Step c: 2- (4-Chloro-3-methoxyphenyl) acetonitrile

To a solution of 4-bromomethyl-1-chloro-2-methoxy-benzene (68.5 g, 0.29 mol) in C ₂ H ₅ OH (90%, 500 mL) was added NaCN (28.5 g, 0.58 mol) . The mixture was stirred at 60 < 0 > C overnight. Evaporation of the ethanol and the residue was dissolved in H ₂ O. The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and purified by column chromatography on silica gel (petroleum ether / EtOAc 30: 1) to give 2- (4-chloro-3-methoxyphenyl) acetonitrile 25 g, 48%). ¹ H NMR (400 MHz, CDCl ₃ )? 7.36 (d, J = 8 Hz, 1H), 6.88-6.84 (m, 2H), 3.92 (s, 3H), 3.74 (s, 2H). ¹³ C NMR (100 MHz, CDCl ₃ )? 155.4, 130.8, 129.7, 122.4, 120.7, 117.5, 111.5, 56.2, 23.5.

D. (4 -Chloro- 3 -hydroxy - phenyl ) -acetonitrile

BBr ₃ (16.6 g, 66 mmol) was slowly added to a solution of 2- (4-chloro-3-methoxyphenyl) acetonitrile (12 g, 66 mmol) in DCM (120 mL) under N ₂ at -78 ° C. The reaction temperature was gradually raised to room temperature. The reaction mixture was stirred overnight and then poured into ice water. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL x 3). To afford the acetonitrile (9.3g, 85%) - the combined organic layers were washed with water, brine, dried with Na ₂ SO _4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl). ^{1 H NMR (300 MHz, CDCl} 3) δ 7.34 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd, J = 2.1, 8.4 Hz, 1 H ), 5.15 (br s, 1 H), 3.72 (s, 2 H).

E. 1- (3- ( hydroxymethyl ) -4 -methoxyphenyl ) cyclopropanecarboxylic acid

Step a: 1- (4-Methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a solution of l- (4-methoxy-phenyl) -cyclopropanecarboxylic acid (50.0 g, 0.26 mol) in MeOH (500 mL) was added toluene-4-sulfonic acid monohydrate (2.5 g, 13 mmol) at room temperature. The reaction mixture was heated to reflux for 20 hours. Evaporation in vacuo removed MeOH and EtOAc (200 mL) was added. The organic layer was washed with saturated aqueous NaHCO ₃ (100 mL) and brine, dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give 1- (4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (53.5 g, 99%). ^{_{1 H NMR (CDCl 3, 400}} MHz) δ 7.25-7.27 (m, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H), 3.62 (s, 3 H), 1.58 (m, 2 H), 1.15 (m, 2 H).

Step b: l- (3-Chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

(- 4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (30.0g, 146mmol) and TiCl ₄ (8.30g, 43.5 at 5 ℃ to a solution of MOMCl (29.1g, 364mmol) 1- in CS ₂ (300㎖) mmol) were added. The reaction mixture was heated at 30 < 0 > C for 1 day and poured into ice water. The mixture was extracted with CH ₂ Cl ₂ (150 mL × 3). The combined organic extracts were evaporated in vacuo to give crude 1- (3-chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (38.0 g) which was used in the next step without further purification.

Step c: 1- (3-Hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a suspension of water (350 mL) crude 1- (3-chloromethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (20.0 g) at room temperature Bu ₄ NBr (4.0 g) and Na ₂ CO ₃ g, 0.85 mol). The reaction mixture was heated at 65 < 0 > C overnight. The resulting solution was acidified with aqueous HCl (2 mol / l) and extracted with EtOAc (200 ml x 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO _4, and evaporated in vacuo to give the crude product, which was purified by column (petroleum ether / EtOAc 15: 1) 1- ( 3- hydroxymethyl- 4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.0 g, 39%). ¹ H NMR (CDCl _3, 400 MHz)? 7.23-7.26 (m, 2H), 6.83 (d, J = 8.0 Hz, 1H) 3.62 (s, 3 H), 1.58 (q, J = 3.6 Hz, 2 H), 1.14-1.17 (m, 2 H).

Step d: l- [3- ( tert- Butyl-dimethyl-silanyloxymethyl) -4-methoxy-phenyl] cyclopropanecarboxylic acid methyl ester

To a solution of l- (3-hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.0 g, 34 mmol) in CH ₂ Cl ₂ (100 mL) at room temperature was added imidazole (5.8 g, 85 mmol) And TBSCl (7.6 g, 51 mmol). The mixture was stirred at room temperature overnight. The mixture was washed with brine, dried over anhydrous Na ₂ SO _4, and evaporated in vacuo to give the crude product, which was purified by column (petroleum ether / EtOAc 30: 1) 1- [ 3- (3 -tert-butyl- Dimethyl-silanyloxymethyl) -4-methoxy-phenyl] -cyclopropanecarboxylic acid methyl ester (6.7 g, 56%). ^{_{1 H NMR (CDCl 3, 400}} MHz) δ 7.44-7.45 (m, 1 H), 7.19 (dd, J = 2.0, 8.4 Hz, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 4.75 (s, 3 H), 3.62 (s, 3 H), 1.57-1.60 (m, 2 H), 1.15-1.18 , 0.11 (s, 6 H).

Step e: 1- (3-Hydroxymethyl-4-methoxy-phenyl) -cyclopropanecarboxylic acid

To a solution of l- [3- ( tert- butyl-dimethyl-silanyloxymethyl) -4-methoxy-phenyl] -cyclopropanecarboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 ml) (10㎖) was added a solution of _{LiOH.H 2 O (1.50g, 35.7mmol)} . The reaction mixture was stirred overnight at 40 < 0 > C. MeOH was removed by evaporation under vacuum. AcOH (1 mol / L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na ₂ SO _4, and evaporated in vacuo 1- (3-Hydroxymethyl-4-methoxy-phenyl) propan-carboxylic acid (5.3g) Respectively.

F. 2- (3- Fluoro- 4 -methoxyphenyl ) acetonitrile

To a suspension of t-BuOK (25.3 g, 0.207 mol) in THF (150 ml) was added a solution of TosMIC (20.3 g, 0.104 mol) in THF (50 ml) at -78 deg. The mixture was stirred for 15 min and treated dropwise with a solution of 3-fluoro-4-methoxy-benzaldehyde (8.00 g, 51.9 mmol) in THF (50 mL) Respectively. Methanol (50 ml) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to give a crude product which was dissolved in water (200 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give the crude product which was purified by column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (3-fluoro-4-methoxyphenyl) acetonitrile 5.0 g, 58%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.02-7.05 (m, 2 H), 6.94 (t, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.67 (s, 2H). ^{13 C NMR (100 MHz, CDCl} 3) δ 152.3, 147.5, 123.7, 122.5, 117.7, 115.8, 113.8, 56.3, 22.6.

G. 2- (3 -Chloro- 4 -methoxyphenyl ) acetonitrile

To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added a solution of TosMIC (3.9 g, 20 mmol) in THF (10 mL) at -78 ° C. The mixture was stirred for 10 min and treated dropwise with a solution of 3-chloro-4-methoxy-benzaldehyde (1.65 g, 10 mmol) in THF (10 ml) and stirring was continued at -78 ° C for 1.5 h. Methanol (10 ml) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to give a crude product which was dissolved in water (20 mL). The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give the crude product which was purified by column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (3-chloro-4- methoxyphenyl) acetonitrile g, 83%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.33 (d, J = 2.4 Hz, 1 H), 7.20 (dd, J = 2.4, 8.4 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H ), 3.91 (s, 3 H), 3.68 (s, 2 H). ¹³ C NMR (100 MHz, CDCl ₃ )? 154.8, 129.8, 127.3, 123.0, 122.7, 117.60, 112.4, 56.2, 22.4.

H. 1- (3,3-Dimethyl-2,3 -dihydrobenzofuran -5-yl) cyclopropanecarboxylic acid

Step a: 1- (4-Hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester

To a solution of methyl 1- (4-methoxyphenyl) cyclopropanecarboxylate (10.0 g, 48.5 mmol) in DCM (80 mL) was added EtSH (16 mL) to an ice bath. Mixture was stirred for 20 minutes at 0 ℃ Next, AlCl ₃ (19.5g, 0.15mmol) was added slowly at 0 ℃. The mixture was stirred at 0 < 0 > C for 30 minutes. The reaction mixture was poured into ice water, the organic layer was separated and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic layers were washed with H ₂ O, brine, dried over Na ₂ SO ₄ and evaporated in vacuo to give 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (8.9 g, 95% Respectively. ¹ H NMR (400 MHz, CDCl ₃ )? 7.20-7.17 (m, 2H), 6.75-6.72 (m, 2H), 5.56 (m, 2 H), 1.17-1.15 (m, 2 H).

Step b: Preparation of 1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecarboxylic acid methyl ester

Was added NIS (15.6g, 69mmol) to a solution of cyclopropanecarboxylic acid methyl ester _{(8.9g, 46mmol) - CH 3} CN (80㎖) of 1- (4-hydroxyphenyl). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 10: 1) to give 1- (4-hydroxy-3,5-diiodo-phenyl) -cyclopropanecarboxylic acid methyl ester 3.5 g, 18%). ¹ H NMR (400 MHz, CDCl ₃ )? 7.65 (s, 2H), 5.71 (s, 1H), 3.63 (s, 3H), 1.59-1.56 , 2 H).

Step c: l- [3,5-Diiodo-4- (2-methyl-allyloxy) -phenyl] -cyclopropanecarboxylic acid methyl ester

(3.2 g, 7.2 mmol), 3-chloro-2-methyl-propene (1.0 g, 7.2 mmol) in acetone g, 11 mmol), K ₂ CO ₃ (1.2 g, 8.6 mmol) and NaI (0.1 g, 0.7 mmol) was stirred overnight at 20 ° C. The solid was filtered and the filtrate was concentrated in vacuo to give 1- [3,5-diiodo-4- (2-methyl-allyloxy) -phenyl] -cyclopropane-carboxylic acid methyl ester (3.5 g, 97% . ¹ H NMR (300 MHz, CDCl ₃ )? 7.75 (s, 2H), 5.26 (s, 1H), 5.06 , 1.98 (s, 3H), 1.62-1.58 (m, 2H), 1.18-1.15 (m, 2H).

Step d: l- (3,3-Dimethyl-2,3-dihydro-benzofuran-5-yl) -cyclopropanecarboxylic acid methyl ester

Toluene (15㎖) of 1- [3,5-di-iodo-4- (2-methyl-allyl) -phenyl] - cyclopropane-carboxylic acid To a solution of Bu ₃ SnH methyl ester (3.5g, 7.0mmol) (2.4 g, 8.4 mmol) and AIBN (0.1 g, 0.7 mmol). The mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 20: 1) to give 1- (3,3-dimethyl-2,3-dihydro-benzofuran- -Cyclopropanecarboxylic acid methyl ester (1.05 g, 62%). ¹ H NMR (400 MHz, CDCl ₃ )? 7.10-7.07 (m, 2H), 6.71 (d, J = 8 Hz, 1H), 4.23 1.58-1.54 (m, 2H), 1.34 (s, 6H), 1.17-1.12 (m, 2H).

Step e: 1- (3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid

To a solution of l- (3,3-dimethyl-2,3-dihydro-benzofuran-5-yl) -cyclopropanecarboxylic acid methyl ester (1 g, 4 mmol) in MeOH (10 ml) was added LiOH (0.40 g, 9.5 mmol ) Was added. The mixture was stirred overnight at 40 < 0 > C. The pH was adjusted to 5 by slowly adding HCl (10%). The resulting mixture was extracted with ethyl acetate (10 ml x 3). The extract was washed with brine, dried over Na ₂ SO _4. The solvent was removed in vacuo and the crude product was purified by preparative HPLC to give 1- (3,3-dimethyl-2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid (0.37 g, 41% . ¹ H NMR (400 MHz, CDCl ₃ )? 7.11-7.07 (m, 2H), 6.71 (d, J = 8 Hz, 1H), 4.23 ), 1.32 (s, 6H), 1.26-1.23 (m, 2H).

I. 2- (7 -Methoxybenzo [d] [1,3] dioxol -5-yl) acetonitrile

Step a: 3,4-Dihydroxy-5-methoxybenzoate

To a solution of water (1000 ml) 3,4,5-trihydroxy-benzoic acid methyl ester (50 g, 0.27 mol) and Na ₂ B ₄ O ₇ (50 g) was added Me ₂ SO ₄ (120 ml) and aqueous NaOH solution 25%, 200 ml) was added continuously at room temperature. The mixture was stirred at room temperature for 6 hours and then cooled to 0 < 0 > C. The mixture was acidified to pH ~ 2 with concentrated H ₂ SO ₄ and then filtered. The filtrate was extracted with EtOAc (500 mL x 3). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%) which was further purified Respectively.

Step b: Methyl 7-methoxybenzo [d] [1,3] dioxole-5-carboxylate

To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g, 0.078 mol) in acetone (500 mL) was added CH ₂ BrCl (34.4 g, 0.27 mol) and K ₂ CO ₃ 75g, 0.54mol) was added. The resulting mixture was heated to reflux for 4 hours. The mixture was cooled to room temperature, filtered the solid K ₂ CO _3. The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with water, dried over anhydrous Na ₂ SO _4, and evaporated under reduced pressure to give the crude product, and this, column chromatography on silica gel (petroleum ether / ethyl acetate = 10: 1) to give methyl 7-methoxy L, 3] dioxol-5-carboxylate (12.6 g, 80%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.32 (s, 1 H), 7.21 (s, 1H), 6.05 (s, 2H), 3.93 (s, 3H), 3.88 (s, 3H).

Step c: (7-Methoxybenzo [d] [1,3] dioxol-5-yl) methanol

To a solution of methyl 7-methoxybenzo [d] [1,3] dioxol-5-carboxylate (13.9 g, 0.040 mol) in THF (100 ml) was added LiAlH ₄ (3.1 g, 0.080 mol) . The mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 C and treated successively with water (3.1 g) and NaOH (10%, 3.1 ml). The slurry was filtered and washed with THF. The combined filtrates were evaporated under reduced pressure to give (7-methoxy-benzo [d] [1,3] dioxol-5-yl) methanol (7.2 g, 52%). ^{1 H NMR (400 MHz, CDCl} 3) δ 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2 H), 4.57 (s, 2 H), 3.90 (s, 3 H).

Step d: 6- (Chloromethyl) -4-methoxybenzo [d] [1,3] dioxole

To a solution of SOCl ₂ (150 ml) was added (7-methoxybenzo [d] [1,3] dioxol-5-yl) methanol (9.0 g, 54 mmol) at 0 ° C. The mixture was stirred for 0.5 hour. Excess of SoCl ₂ was evaporated under reduced pressure to give a crude product which was basified to pH ~ 7 using saturated aqueous NaHCO ₃ . The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and evaporated to give 6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxole (10.2 g 94% It was used in the next step without purification. ¹ H NMR (400 MHz, CDCl ₃ )? 6.58 (s, 1H), 6.57 (s, 1H), 5.98 .

Step e: 2- (7-Methoxybenzo [d] [1,3] dioxol-5-yl) acetonitrile

To a solution of 6- (chloromethyl) -4-methoxybenzo [d] [1,3] dioxole (10.2 g, At room temperature was added NaCN (2.43 g, 50 mmol). The mixture was stirred for 3 hours and poured into water (500 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated to afford crude product, and the ether washed with 2- (7-methoxy-benzo [d] [1,3] dioxol-5-yl) acetonitrile Nitrile (4.6 g, 45%). ¹ H NMR (400 MHz, CDCl ₃ )? 6.49 (s, 2H), 5.98 (s, 2H), 3.91 (s, 3H), 3.65 (s, 2H). ¹³ C NMR (400 MHz, CDCl ₃ )? 148.9, 143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1.

J. 1- ( Benzofuran -5-yl) cyclopropanecarboxylic acid

Step a: 1- [4- (2,2-Diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid

To a stirred solution of 1- (4-hydroxy-phenyl) -cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF (50 ml) at 0 C was added sodium hydride (6.7 g, 170 mmol, 60% Were added. After hydrogen evolution ceased, 2-bromo-l, l-diethoxy-ethane (16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction was stirred at 160 < 0 > C for 15 hours. The reaction mixture was poured into ice (100 g) and extracted with CH ₂ Cl ₂ . The combined organics were dried over Na ₂ SO ₄ . The solvent was removed in vacuo to give crude 1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid (10 g) which was used directly in the next step without further purification.

Step b: Preparation of 1-benzofuran-5-yl-cyclopropanecarboxylic acid

To a suspension of crude 1- [4- (2,2-diethoxy-ethoxy) -phenyl] -cyclopropanecarboxylic acid (20 g, - 65 mmol) in xylene (100 ml) was added PPA (22.2 g, 64.9 mmol) . The mixture was heated to reflux (140 < 0 > C) for 1 h, then cooled at room temperature and triturated from PPA. Evaporation of the solvent in vacuo gave the crude product which was purified by preparative HPLC to give 1- (benzofuran-5-yl) cyclopropanecarboxylic acid (1.5 g, 5%). ^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.25 (br s, 1 H), 7.95 (d, J = 2.8 Hz, 1 H), 7.56 (d, J = 2.0 Hz, 1 H), 7.47 ( d, J = 11.6 Hz, 1 H), 7.25 (dd, J = 2.4, 11.2 Hz, 1 H), 6.89 (d, J = 1.6 Hz, 1 H), 1.47-1.44 (m, 2 H), 1.17 -1.14 (m, 2H).

K. 1- (2,3 - Dihydrobenzofuran - 5-yl) cyclopropanecarboxylic acid

MeOH (10㎖) was added to a solution of l (benzofuran-5-yl) cyclopropanecarboxylic acid PtO ₂ (140㎎, 20%) at room temperature was added (700㎎, 3.47mmol). The stirred reaction mixture was hydrogenated (1 atm) under hydrogen at 10 < 0 > C for 3 days. The reaction mixture was filtered. The solvent was evaporated in vacuo to give the crude product which was purified by preparative HPLC to give 1- (2,3-dihydrobenzofuran-5-yl) cyclopropanecarboxylic acid (330 mg, 47%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.20 (s, 1 H), 7.10 (d, J = 10.8 Hz, 1 H), 6.73 (d, J = 11.2 Hz, 1 H), 4.57 (t, J = 11.6 Hz, 2 H), 3.20 (t, J = 11.6 Hz, 2H), 1.67-1.63 (m, 2H), 1.25-1.21 (m, 2H).

L. 2- (2,2- Dimethylbenzo [d] [1,3] dioxol -5-yl) acetonitrile

Step a: Preparation of (3,4-dihydroxy-phenyl) -acetonitrile

CH ₂ Cl ₂ (15㎖) of benzo [1,3] dioxol-5-yl-acetonitrile _{(0.50g, 3.1mmol) BBr 3 (} 0.78g, 3.1mmol) under N ₂ at -78 ℃ To a solution of Was added dropwise. The mixture was slowly warmed to room temperature and stirred overnight. H ₂ O (10 mL) was added to quench the reaction and the CH ₂ Cl ₂ layer was separated. The aqueous phase was extracted with CH ₂ Cl ₂ (2 x 7 mL). The combined organics were washed with brine, dried with Na ₂ SO _4, silica gel column chromatography (petroleum ether / EtOAc 5: 1) to give a white solid (3, 4-dihydroxy-phenyl) -acetonitrile (0.25 g, 54%). ^{_{1 H NMR (DMSO- d 6,}} 400 MHz) δ 9.07 (s, 1 H), 8.95 (s, 1 H), 6.68-6.70 (m, 2 H), 6.55 (dd, J = 8.0, 2.0 Hz, 1 H), 3.32 (s, 2 H).

Step b: 2- (2,2-Dimethylbenzo [d] [1,3] dioxol-5-yl) acetonitrile

To a solution of (3,4-dihydroxy-phenyl) -acetonitrile (0.2 g, 1.3 mmol) in toluene (4 ml) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH , 0.065 mmol) was added. The mixture was heated to reflux overnight. The reaction mixture was evaporated to remove the solvent and the residue was dissolved in ethyl acetate. The organic layer was washed with NaHCO ₃ solution, H ₂ O, brine, and dried over Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to give a residue which was purified by column chromatography on silica gel (petroleum ether / EtOAc 10: 1) to give 2- (2,2-dimethylbenzo [d] [1,3] dioxol- -Yl) acetonitrile (40 mg, 20%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 6.68 - 6.71 (m, 3 H), 3.64 (s, 2 H), 1.67 (s, 6 H).

M. 2- (3- ( Benzyloxy ) -4 -chlorophenyl ) acetonitrile

Step a: (4-Chloro-3-hydroxy-phenyl) acetonitrile

BBr ₃ (16.6 g, 66 mmol) was slowly added to a solution of 2- (4-chloro-3-methoxyphenyl) acetonitrile (12 g, 66 mmol) in DCM (120 mL) under N ₂ at -78 ° C. The reaction temperature was gradually raised to room temperature. The reaction mixture was stirred overnight and then poured into ice water. The organic layer was separated and the aqueous layer was extracted with DCM (40 mL x 3). To afford the acetonitrile (9.3g, 85%) - the combined organic layers were washed with water, brine, dried with Na ₂ SO _4, and concentrated under vacuum to give (4-chloro-3-hydroxy-phenyl). ^{1 H NMR (300 MHz, CDCl} 3) δ 7.34 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd, J = 2.1, 8.4 Hz, 1 H ), 5.15 (br s, 1 H), 3.72 (s, 2 H).

Step b: 2- (3- (Benzyloxy) -4-chlorophenyl) acetonitrile

K ₂ CO ₃ (10.2 g, 74 mmol) and BnBr (7.6 g, 44 mmol) were added to a solution of (4-chloro-3-hydroxy-phenyl) acetonitrile (6.2 g, 37 mmol) in CH ₃ CN . The mixture was stirred at room temperature overnight. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 50: 1) to give 2- (3- (benzyloxy) -4-chlorophenyl) acetonitrile (5.6 g, 60%). ¹ H NMR (400 MHz, CDCl ₃ )? 7.48-7.32 (m, 6 H), 6.94 (d, J = 2 Hz, 2H), 6.86 (dd, J = 2.0,8.4 Hz, 1H) (s, 2 H), 3.71 (s, 2 H).

N, 2- ( Quinoxaline Yl) Acetonitrile

Step a: 6-Methylquinoxaline

To a solution of 4-methylbenzene-1,2-diamine (50.0 g, 0.41 mol) in isopropanol (300 ml) was added a solution of glyoxal (40% in water, 65.3 g, 0.45 mol) at room temperature. The reaction mixture was heated at 80 < 0 > C for 2 hours and then evaporated in vacuo to give 6-methylquinoxaline (55 g, 93%) which was used directly in the next step. ¹ H NMR (300 MHz, CDCl ₃ )? 8.77 (dd, J = 1.5, 7.2 Hz, 2H), 7.99 (d, J = 8.7 Hz, 1H) , J = 1.5, 8.4 Hz, 1H), 2.59 (s, 3H).

Step b: 6-Bromomethylquinoxaline

To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCl ₄ (80 mL) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated to reflux for 2 hours. After cooling, the mixture was evaporated in vacuo to give a yellow solid which was extracted with petroleum ether (50 mL x 5). The extract was concentrated in vacuo. The organics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g) which was used directly in the next step. ¹ H NMR (300 MHz, CDCl ₃ )? 8.85-8.87 (m, 2H), 8.10-8.13 (m, 2H), 7.82 (dd, J = 2.1, 8.7 Hz, 1H) 2 H).

Step c: 2- (Quinoxalin-6-yl) acetonitrile

To a solution of crude 6-bromomethylquinoxaline (36.0 g) in 95% ethanol (200 ml) was added NaCN (30.9 g, 0.63 mol) at room temperature. The mixture was heated at 50 < 0 > C for 3 h and then concentrated in vacuo. Water (100 ml) and ethyl acetate (100 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried with Na ₂ SO _4, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / EtOAc 10: 1) to give 2- (quinoxalin-6-yl) acetonitrile (7.9 g, 23% for two steps). ¹ H NMR (300 MHz, CDCl ₃ )? 8.88-8.90 (m, 2H), 8.12-8.18 (m, 2H), 7.74 (dd, J = 2.1, 8.7 Hz, 1H) 2 H). MS (ESI) m / z (M + H) < ⁺ & gt ^; 170.0.

O. 2- (Quinolin-6-yl) acetonitrile

Step a: 6-Bromomethylquinoline

NBS (2.92 g, 16.5 mmol) and benzoyl peroxide (BP, 0.36 g, 1.5 mmol) were added to a solution of 6-methylquinoline (2.15 g, 15.0 mmol) in CCl ₄ (30 mL) at room temperature. The mixture was heated to reflux for 2 hours. After cooling, the mixture was evaporated in vacuo to give a yellow solid which was extracted with petroleum ether (30 mL x 5). The extract was concentrated in vacuo to give crude 6-bromomethylquinoline (1.8 g) which was used directly in the next step.

Step b: 2- (Quinolin-6-yl) acetonitrile

To a solution of crude 6-bromomethylquinoline (1.8 g) in 95% ethanol (30 ml) was added NaCN (2.0 g, 40.8 mmol) at room temperature. The mixture was heated at 50 < 0 > C for 3 h and then concentrated in vacuo. Water (50 ml) and ethyl acetate (50 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The combined crude product was purified by column (petroleum ether / EtOAc 5: 1) to give 2- (quinolin-6-yl) acetonitrile (0.25 g, 8% for two steps). ¹ H NMR (300 MHz, CDCl ₃ )? 8.95 (dd, J = 1.5, 4.2 Hz, 1H), 8.12-8.19 (m, 2H), 7.85 2.1, 8.7 Hz, 1H), 7.46 (q, J = 4.2 Hz, 1H), 3.96 (s, 2H). MS (ESI) m / e (M + H) < ⁺ & gt ^; 169.0.

P. 2- (2,3 -Dihydrobenzo [b] [1,4] dioxin -6-yl) acetonitrile

Step a: 2,3-Dihydro-benzo [1,4] dioxine-6-carboxylic acid ethyl ester

To a suspension of Cs ₂ CO ₃ (270 g, 1.49 mol) in DMF (1000 ml) was added at room temperature 3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane , 0.29 mol) was added. The resulting mixture was stirred at 80 < 0 > C overnight and then poured into ice water. The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water (200 mL x 3) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column on silica gel (petroleum ether / ethyl acetate 50: 1) to give 2,3-dihydro-benzo [1,4] dioxine-6-carboxylic acid ethyl ester (18 g, 29%). ¹ H NMR (300 MHz, CDCl ₃ )? 7.53 (dd, J = 1.8, 7.2 Hz, 2H), 6.84-6.87 (m, 1H), 4.22-4.34 J = 7.2 Hz, 3 H).

Step b: (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -methanol

Benzo [1,4] dioxin-6-carboxylic acid ethyl ester (15g - THF (20㎖) of 2,3- dihydro-LAH in THF (10ml) under N ₂ eseo 0 ℃ To a suspension of (2.8g, 74mmol) , 72 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour and then carefully quenched with water (2.8 mL) and NaOH (10%, 28 mL) while cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to give (2,3-dihydro-benzo [1,4] dioxin-6-yl) -methanol (10.6 g). ^{1 H NMR (300 MHz, DMSO} -d 6) δ 6.73-6.78 (m, 3 H), 5.02 (t, J = 5.7 Hz, 1 H), 4.34 (d, J = 6.0 Hz, 2 H), 4.17 -4.20 (m, 4 H).

Step c: 6-Chloromethyl-2,3-dihydro-benzo [1,4] dioxin

A mixture of (2,3-dihydro-benzo [1,4] dioxin-6-yl) methanol (10.6 g) in SOCl ₂ (10 ml) was stirred at room temperature for 10 minutes and then poured into ice water. The organic layer was separated and the aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with NaHCO ₃ (saturated solution), water and brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 6-chloromethyl-2,3-dihydro-benzo [1,4] di Auxin (12 g, 88% for two steps) was obtained, which was used directly in the next step.

Step d: 2- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile

A mixture of 6-chloromethyl-2,3-dihydro-benzo [1,4] dioxine (12.5 g, 67.7 mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) Lt; / RTI > The mixture was poured into water (150 ml) and extracted with dichloromethane (50 ml x 4). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 50: 1) to give 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) acetonitrile as a yellow oil 10.2 g, 86%). ¹ H-NMR (300 MHz, CDCl ₃ )? 6.78-6.86 (m, 3 H), 4.25 (s, 4 H), 3.63 (s, 2 H).

Q. 2- (2,2,4,4- Tetrafluoro- 4H- benzo [d] [1,3] dioxin -6-yl) acetonitrile

Step a: 2,2,4,4-Tetrafluoro-4H-benzo [1,3] dioxine-6-carboxylic acid methyl ester

MeOH (20㎖), MeCN (30㎖ ) and Et ₃ N (10㎖) -4H- benzo To a solution of 6-bromo -2,2,4,4- tetrahydro-fluoro [1, 3] dioxine (4.75g , 16.6mmol) and Pd (PPh _{3) 4} ((oil bath temperature) under carbon monoxide atmosphere at 75 ℃ (55psi) to a suspension of 950㎎, 8.23mmol) was stirred overnight. The cooled reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column (petroleum ether) to give 2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-carboxylic acid methyl ester (3.75 g, 85% . _{^{1 H NMR (CDCl 3, 300}} MHz) δ 8.34 (s, 1 H), 8.26 (dd, J = 2.1, 8.7 Hz, 1 H), 7.22 (d, J = 8.7 Hz, 1 H), 3.96 (s , 3 H).

Step b: (2,2,4,4-Tetrafluoro-4H-benzo [1,3] dioxin-6-yl)

To a suspension of LAH (2.14 g, 56.4 mmol) in anhydrous THF (200 mL) was added a solution of 2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin -6-carboxylic < / RTI > acid methyl ester (7.50 g, 28.2 mmol). After stirring at 0 < 0 > C for 1 hour, the reaction mixture was treated with water (2.14 g) and 10% NaOH (2.14 ml). The slurry was filtered and washed with THF. The combined filtrate was evaporated to dryness to give crude (2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) -methanol (6.5 g) . ¹ H NMR (CDCl ₃ , 300 MHz)? 7.64 (s, 1H), 7.57-7.60 (m, 1H), 7.58 (d, J = 8.7 Hz, 1H), 4.75 (s, 2H).

Step c: Preparation of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3]

A mixture of (2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) -methanol (6.5 g) in thionyl chloride (75 ml) was heated to reflux overnight. The resulting mixture was concentrated in vacuo. The residue was basified with aqueous saturated NaHCO _3. The aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6.2 g of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3] , Which was used directly in the next step. ¹ H NMR (CDCl ₃ , 300 MHz)? 7.65 (s, 1H), 7.61 (dd, J = 2.1,8.7 Hz, 1H), 7.15 , 2 H).

Step d: (2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) -acetonitrile

A mixture of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo [1,3] dioxine (6.2 g) and NaCN (2.07 g, 42.3 mmol) in DMSO (50 ml) Lt; / RTI > for 2 h. The reaction mixture was poured into ice and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and evaporated to a crude product, and Sud, this column of silica gel (petroleum ether / EtOAc 10: 1) to obtain (2,2-difluoro-benzo [1, 3] dioxol-5-yl) -acetonitrile (4.5 g, 68% over three steps). _{^{1 H NMR (CDCl 3, 300}} MHz) δ 7.57-7.60 (m, 2 H), 7.20 (d, J = 8.7 Hz, 1 H), 3.82 (s, 2 H).

R. 2- (4H- benzo [d] [1,3] dioxin -7-yl) acetonitrile

Step a: Preparation of (3-hydroxyphenyl) acetonitrile

To a solution of (3-methoxyphenyl) acetonitrile (150 g, 1.03 mol) in CH ₂ Cl ₂ (1000 ml) was added BBr ₃ (774 g, 3.09 mol) dropwise at -70 ° C. The mixture was stirred and slowly warmed to room temperature. Water (300 mL) was added at 0 < 0 > C. The resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over anhydrous Na ₂ SO ₄ and, filtered and evaporated in vacuo. The crude residue was purified by column (petroleum ether / EtOAc 10: 1) to give (3-hydroxyphenyl) acetonitrile (75.0 g, 55%). ^{_{1 H NMR (CDCl 3, 300}} MHz) δ 7.18-7.24 (m, 1 H), 6.79-6.84 (m, 3 H), 3.69 (s, 2 H).

Step b: 2- (4H-benzo [d] [1,3] dioxin-7-yl) acetonitrile

To a solution of (3-hydroxyphenyl) acetonitrile (75.0g, 0.56mol) in toluene (750ml) was added paraformaldehyde (84.0g, 2.80mol) and toluene-4-sulfonic acid monohydrate (10.7g, 56.0 mmol) was added. The reaction mixture was heated to reflux for 40 minutes. The toluene was removed by evaporation. Water (150 ml) and ethyl acetate (150 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous Na ₂ SO _4, and evaporated in vacuo. The residue was separated by preparative HPLC to give 2- (4H-benzo [d] [1,3] dioxin-7-yl) acetonitrile (4.7 g, 5%). ^{1 H NMR (300 MHz, CDCl} 3) δ 6.85-6.98 (m, 3 H), 5.25 (d, J = 3.0 Hz, 2 H), 4.89 (s, 2 H), 3.69 (s, 2 H).

S. 2- (4H- benzo [d] [1,3] dioxin -6-yl) acetonitrile

To a solution of (4-hydroxyphenyl) acetonitrile (17.3g, 0.13mol) in toluene (350ml) was added paraformaldehyde (39.0g, 0.43mmol) and toluene-4-sulfonic acid monohydrate (2.5g, 13 mmol) was added. The reaction mixture was heated to reflux for 1 hour. The toluene was removed by evaporation. Water (150 ml) and ethyl acetate (150 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried with Na ₂ SO _4, and concentrated in vacuo. The residue was separated by preparative HPLC to give 2- (4H-benzo [d] [1,3] dioxin-6-yl) acetonitrile (7.35 g, 32%). ¹ H NMR (400 MHz, CDCl ₃ )? 7.07-7.11 (m, 1H), 6.95-6.95 (m, 1H), 6.88 (d, J = 11.6 Hz, 1H) ), 4.89 (s, 2 H), 3.67 (s, 2 H).

T. Preparation of 2- (3- ( benzyloxy ) -4 -methoxyphenyl ) acetonitrile

To a suspension of t-BuOK (20.15 g, 0.165 mol) in THF (250 mL) at -78 <0> C was added a solution of TosMIC (16.1 g, 82.6 mmol) in THF (100 mL). The mixture was stirred for 15 min and treated dropwise with a solution of 3-benzyloxy-4-methoxy-benzaldehyde (10.0 g, 51.9 mmol) in THF (50 mL) . Methanol (50 mL) was added to the cooled reaction mixture. The mixture was heated to reflux for 30 minutes. The solvent of the reaction mixture was removed to give a crude product which was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic layers were dried and evaporated under reduced pressure to give the crude product which was purified by column chromatography (petroleum ether / EtOAc 10: 1) to give 2- (3- (benzyloxy) -4- methoxyphenyl) Nitrile (5.0 g, 48%). ^{1 H NMR (300 MHz, CDCl} 3) δ 7.48-7.33 (m, 5 H), 6.89 - 6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s, 3 H), 3.66 (s, 2 H). ¹³ C NMR (75 MHz, CDCl ₃ ) 隆 149.6, 148.6, 136.8, 128.8, 128.8, 128.2, 127.5, 127.5, 122.1, 120.9, 118.2, 113.8, 112.2, 71.2, 56.2, 23.3.

Table 2 below contains a list of carboxylic acid building blocks, either commercially available or prepared by one of the methods described above.

U. 6 -Chloro- 5 -methylpyridin - 2 -amine

Step a: 2,2-Dimethyl- N- (5-methyl-pyridin-2-yl) -propionamide

Anhydrous CH ₂ Cl ₂ (1000㎖) of 5-methyl-2-amine (200g, 1.85mol) ₃ Et N (513㎖, 3.70mol) under N ₂ eseo 0 ℃ To a stirred solution of and 2,2-dimethyl -Propionyl chloride (274 mL, 2.22 mol) was added dropwise. The ice bath was removed and stirring was continued for 2 hours at room temperature. The reaction was poured into ice (2000 g). The organic layer was separated and the remaining aqueous layer was extracted with CH ₂ Cl ₂ (3x). The combined organics were dried over Na ₂ SO ₄ and evaporated to give 350 g of 2,2-dimethyl- N- (5-methyl-pyridin-2-yl) -propionamide, Respectively. ^{1 H NMR (400 MHz, CDCl} 3) δ 8.12 (d, J = 8.4 Hz, 1 H), 8.06 (d, J = 1.2 Hz, 1 H), 7.96 (s, 1 H), 7.49 (dd, J = 1.6, 8.4 Hz, 1H), 2.27 (s, 1H), 1.30 (s, 9H).

Step b: 2,2-Dimethyl- N- (5-methyl-1-oxy-pyridin-2- yl) -propionamide

To a stirred solution of 2,2-dimethyl- N- (5-methyl-pyridin-2-yl) -propionamide (100 g, 0.52 mol) in AcOH (500 ml) was added 30% H ₂ O ₂ 2.6 mol) was added dropwise. The mixture was stirred at 80 &lt; 0 &gt; C for 12 hours. The reaction mixture was evaporated in vacuo to give 2,2-dimethyl- N- (5-methyl-1-oxy-pyridin-2-yl) -propionamide (80 g, 85% purity). ^{1 H NMR (400 MHz, CDCl} 3) δ 10.26 (br s, 1 H), 8.33 (d, J = 8.4 Hz, 1 H), 8.12 (s, 1 H), 7.17 (dd, J = 0.8, 8.8 Hz, 1H), 2.28 (s, 1H), 1.34 (s, 9H).

Step c: Preparation of N- (6-chloro-5-methyl-pyridin-2-yl) -2,2-dimethyl-

2,2 in anhydrous _{CH 2 Cl 2 (50㎖) -} N - (5- methyl-1-oxy-pyridin-2-yl) propionamide (10g, 48mmol) Et ₃ N at room temperature to a stirred solution of (60 mL, 240 mmol) was added. After stirring for 30 minutes, POCl ₃ (20 mL) was added dropwise to the reaction mixture. The reaction was stirred at 50 &lt; 0 &gt; C for 15 hours. The reaction mixture was poured into ice (200 g). The organic layer was separated and the remaining aqueous layer was extracted with CH ₂ Cl ₂ (3x). The combined organics were dried over Na ₂ SO ₄ . Evaporation of the solvent in vacuo gave the crude product which was purified by chromatography (petroleum ether / EtOAc 100: 1) to give N - (6-chloro-5-methyl-pyridin- -Propionamide &lt; / RTI &gt; (0.5 g, 5%). ^{1 H NMR (400 MHz, CDCl} 3) δ 8.09 (d, J = 8.0 Hz, 1 H), 7.94 (br s, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 2.33 (s, 1 H), 1.30 (s, 9 H).

Step d: 6-Chloro-5-methyl-pyridin-2-ylamine

6 N HCl (20 mL) was added at room temperature to N - (6-chloro-5-methyl-pyridin-2-yl) -2,2- dimethyl-propionamide (4.00 g, 17.7 mmol). The mixture was stirred at 80 &lt; 0 &gt; C for 12 hours. The reaction mixture was basified to pH 8-9 with saturated NaHCO ₃ and the mixture was extracted with CH ₂ Cl ₂ (3x). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give 6-chloro-5-methyl-pyridin-2-ylamine (900 mg, 36%). ^{1 H NMR (400 MHz, CDCl} 3) δ 7.28 (d, J = 8.0 Hz, 1 H), 6.35 (d, J = 8.0 Hz, 1 H), 4.39 (br s, 2 H), 2.22 (s, 3 H). MS (ESI) m / z: 143 (M + H ^& lt ^{; +} & gt ^; ).

V. 6 -Chloro- 5- ( trifluoromethyl ) pyridin-2-amine

2,6-dichloro-3- (trifluoromethyl) pyridine (5.00 g, 23.2 mmol) and 28% aqueous ammonia (150 ml) were placed in a 250 ml autoclave. The mixture was heated at 93 [deg.] C for 21 hours. The reaction was cooled to room temperature and extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and evaporated in vacuo to give a crude product which was purified by column chromatography on silica gel (2-20% EtOAc in petroleum ether as eluent) to give 6-chloro-5 - (trifluoromethyl) pyridin-2-amine (2.1 g, 46% yield). ¹ H NMR (400 MHz, DMSO- d ₆ )? 7.69 (d, J = 8.4 Hz, 1H), 7.13 (br s, 2H), 6.43 (d, J = 8.4 Hz, 1H). MS (ESI) m / z (M + H) &lt; ⁺ & gt ^; 197.2

General process IV : Coupling reaction

One equivalent of the appropriate carboxylic acid was placed in an oven-dried flask under nitrogen. Thionyl chloride (3 eq.) And a catalytic amount of N, N -dimethylformamide were added and the solution was stirred at 60 &lt; 0 &gt; C for 30 min. Excess thionyl chloride was removed in vacuo and the resulting solid was suspended in a minimal amount of anhydrous pyridine. The solution was added to a stirred solution of 1 equivalent of the appropriate amino heterocycle dissolved in a minimal amount of anhydrous pyridine. The resulting mixture was stirred at 110 &lt; 0 &gt; C for 15 hours. The mixture was evaporated to dryness, suspended in dichloromethane and then extracted three times with 1N NaOH. The organic layer was then dried over sodium sulfate, evaporated to dryness and then purified by column chromatography.

W. 1- (benzo [d] [1,3] dioxol-5-yl) - N - (5- bromo-2-yl) cyclopropane-carboxamide (B-1)

1-Benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (2.38 g, 11.5 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (2.5 ml) and N, N -dimethylformamide (0.3 ml) were added and the solution was stirred at 60 &lt; 0 &gt; C for 30 min. Excess thionyl chloride was removed in vacuo and the resulting solid was suspended in 7 ml anhydrous pyridine. The solution was then slowly added to a solution of 5-bromo-pyridin-2-ylamine (2.00 g, 11.6 mmol) suspended in 10 ml anhydrous pyridine. The resulting mixture was stirred at 110 &lt; 0 &gt; C for 15 hours. The mixture was then evaporated to dryness, suspended in 100 mL of dichloromethane and washed with three 25 mL portions of 1 N NaOH. The organic layer was dried over sodium sulfate, evaporated to near dryness and then purified by silica gel column chromatography using dichloromethane as eluent to give pure product (3.46 g, 83%). ESI-MS m / z calc 361.2, found 362.1 (M + 1) ^&lt; + &^gt;; Retention time 3.40 minutes. ^{1 H NMR (400 MHz, DMSO-} d 6) δ 1.06-1.21 (m, 2H), 1.44-1.51 (m, 2H), 6.07 (s, 2H), 6.93-7.02 (m, 2H), 7.10 (d , J = 1.6 Hz, 1H) , 8.02 (d, J = 1.6 Hz, 2H), 8.34 (s, 1H), 8.45 (s, 1H).

X. 1- (benzo [d] [1,3] dioxol-6-yl) - N - (6- bromopyridin-2-yl) cyclopropane-carboxamide (B-2)

5-yl-cyclopropanecarboxylic acid (1.2 g, 5.8 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (2.5 mL) and N, N -dimethylform The amide (0.3 ml) was added and the solution was stirred for 30 min at 60 DEG C. The excess thionyl chloride was removed in vacuo and the resulting solid suspended in 5 ml anhydrous pyridine then the solution was treated with anhydrous pyridine 10 Was added slowly to a solution of 6-bromopyridin-2-amine (1.0 g, 5.8 mmol) suspended in methanol (10 mL) at 0 C. The resulting mixture was stirred at 110 [deg.] C for 15 hours. Suspended in 50 mL of dichloromethane and washed with 20 mL of 1N NaOH three times. The organic layer was dried over sodium sulfate, evaporated to near dryness and then purified by flash chromatography using dichloromethane containing 2.5% triethylamine as eluent Silica gel column chromatography . Purification by our to give the pure product ESI-MS m / z calcd 361.2, found ^{362.1 (M + 1) +;} . Retention time 3.43 minutes ^{1 H NMR (400 MHz, DMSO-} d 6) δ 1.10-1.17 ( m, 2H), 1.42-1.55 (m , 2H), 6.06 (s, 2H), 6.92-7.02 (m, 2H), 7.09 (d, J = 1.6 Hz, 1H), 7.33 (d, J = 7.6 Hz J = 8.0 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.78

The following compounds in Table 3 were prepared in a manner analogous to that described above:

General procedure V: Compound of formula I

A suitable aryl halide (1 eq.) Was dissolved in 1 mL of N, N -dimethylformamide (DMF) in a reaction tube. 0.1 ml (2 eq.) Of an aqueous 2M potassium carbonate solution and a catalytic amount of Pd (dppf) Cl ₂ (0.09 eq.) Were added and the reaction mixture was stirred at 80 &lt; 0 &gt; C for 3 h, Min in a microwave. The resulting material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography.

Y. 1- benzo [1, 3] dioxol-5-yl-cyclopropanecarboxylic acid [5- (2,4-dimethoxy-Fe carbonyl) -pyridin-2-yl] -amide

5-yl-cyclopropanecarboxylic acid (5-bromo-pyridin-2-yl) -amide (36.1 mg, 0.10 mmol) was dissolved in N, N -dimethylformamide &Lt; / RTI &gt; Pd (dppf) Cl ₂ (6.6 mg, 0.0090 mmol) in a catalytic amount was added to the reaction mixture, and the reaction mixture was stirred at 80 ° C for 3 hours Lt; / RTI &gt; The resulting material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography to give the pure product as the trifluoroacetic acid salt. ESI-MS m / z calc 418.2, found 419.0 (M + l) ⁺ . Retention time 3.18 minutes. ^{1 H NMR (400 MHz, CD} 3 CN) δ 1.25-1.29 (m, 2H), 1.63-1.67 (m, 2H), 3.83 (s, 3H), 3.86 (s, 3H), 6.04 (s, 2H) , 6.64-6.68 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 7.03-7.06 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 8.14 (dd , J = 8.9, 2.3 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.65 (s, 1H).

Z. 1- benzo [1, 3] dioxol-5-yl-cyclopropanecarboxylic acid [6- (4-Dimethylamino-Fe carbonyl) -pyridin-2-yl] -amide

(36 mg, 0.10 mmol) was dissolved in N, N -dimethylformamide (1 mL) in a reaction tube , &Lt; / RTI &gt; 0.1 ml of a 2M potassium carbonate aqueous solution and (Pd (dppf) Cl ₂ (6.6 mg, 0.0090 mmol) were added and the reaction mixture was stirred at 80 ° C for 3 hours The resulting material was cooled to room temperature, filtered and purified by reverse phase preparative liquid chromatography to give the pure product as the trifluoroacetic acid salt. ESI-MS m / z calcd 401.2, found 402.5 (M + l ) ⁺ . Retention time 2.96 min ¹ H NMR (400 MHz, CD ₃ CN)? 1.23-1.27 (m, 2H), 1.62-1.66 (m, 2H), 3.04 ), 6.88-6.90 (m, 2H), 6.93-6.96 (m, 1H), 7.05-7.07 (m, 2H), 7.53-7.56 (m, 1 H), 8.34 (s, 1 H).

Additional boronic acid esters, which are not commercially available, were prepared using the following reaction scheme.

AA. 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) phenyl] sulfonyl carbonyl piperazine

Step a: 1- (4-Bromophenylsulfonyl) -4-methylpiperazine

A solution of 4-bromobenzene-1-sulfonyl chloride (256 mg, 1.00 mmol) in 1 mL of dichloromethane was treated with 5 mL of a saturated aqueous sodium bicarbonate solution, dichloromethane (5 mL) and 1-methylpiperazine Was slowly added to a vial (40 mL) containing the compound of formula (I) (1.00 mmol). The reaction was stirred overnight at room temperature. The phases were separated and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the required product which was used in the next step without further purification. ESI-MS m / z calc 318.0, found 318.9 (M + l) ⁺ . Retention time 1.30 min. ^{1 H NMR (300 MHz, CDCl} 3) δ 7.65 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 3.03 (t, J = 4.2 Hz, 4H), 2.48 (t , &Lt; / RTI &gt; J = 4.2 Hz, 4H), 2.26 (s, 3H).

Step b: 1-Methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) phenyl] sulfonyl-

50㎖ round bottom in N, N flask-1 in dimethylformamide (6㎖) (4- bromophenyl-sulfonyl) -4-methylpiperazine (110㎎, 0.350mmol), bis (pinacolato) Diboron (93 mg, 0.37 mmol), palladium acetate (6 mg, 0.02 mmol) and potassium acetate (103 mg, 1.05 mmol). The mixture was degassed by mild bubbling argon through the solution at room temperature for 30 minutes. The mixture was then heated at 80 &lt; 0 &gt; C under argon until the reaction was complete (4 h). The desired product, 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -sulfonyl- The re-product, 4- (4-methylpiperazin-1-ylsulfonyl) -phenyl-phenylsulfonyl-4-methylpiperazine, was obtained in a ratio of 1: 2 as indicated by LC / MS analysis. The mixture was used without further purification.

BB. 4,4,5,5- tetramethyl- 2- (4- (2- ( methylsulfonyl ) ethyl) phenyl ) -1,3,2 -dioxaborolane

Step a: 4-Bromophenethyl-4-methylbenzenesulfonate

P -Bromophenethyl alcohol (1.0 g, 4.9 mmol) was added to a 50 ml round bottom flask, followed by pyridine (15 ml). To the clear solution was added p -toluenesulfonyl chloride (TsCl) (1.4 g, 7.5 mmol) as a solid under argon. The reaction mixture was purged with argon and stirred at room temperature for 18 hours. The crude mixture was treated with 1N HCl (20 mL) and extracted with ethyl acetate (5 x 25 mL). Dry the organic fraction with Na ₂ SO _4, filtered, and concentrated to give a 4-bromophenoxy ethyl-4-methyl-benzenesulfonate (0.60g, 35%) as a yellow liquid. ¹ H-NMR (acetone _{- d 6, 300 MHz) δ} 7.64 (d, J = 8.4 Hz, 2H), 7.40-7.37 (d, J = 8.7 Hz, 4H), 7.09 (d, J = 8.5 Hz, 2H ), 4.25 (t, J = 6.9 Hz, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.45 (s, 3H).

Step b: (4-Bromophenethyl) (methyl) sulfan

4-methylbenzenesulfonate (0.354 g, 0.996 mmol) and CH ₃ SNa (0.10 g, 1.5 mmol) were added to a 20 mL round bottom flask and then THF (1.5 mL) and N -methyl- Pyrrolidinone (1.0 ml) was added. The mixture was stirred at room temperature for 48 hours and then treated with a saturated aqueous solution of sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (4 × 10㎖), dried with Na ₂ SO _4, filtered, and concentrated to provide (4-bromophenoxy ethyl) (methyl) to give the 0498] (0.30g, crude product) as a yellow oil Respectively. _{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 7.40 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 2.89-2.81 (m, 2H), 2.74-2.69 (m , &Lt; / RTI &gt; 2H), 2.10 (s, 3H).

Step c: 1-Bromo-4- (2-methylsulfonyl) -ethylbenzene

(4-bromophenyl) - (methyl) sulfan (0.311 g, 1.34 mmol) and oxone (3.1 g, 0.020 mol) were added to a 20 mL round bottom flask and a 1: 1 mixture of acetone / water (10 mL) . The mixture was vigorously stirred at room temperature for 20 hours and then concentrated. The aqueous mixture was extracted with ethyl acetate (3 x 15 mL) and dichloromethane (3 x 10 mL). Combine the organic fractions dried over Na ₂ SO _4, filtered and concentrated to give a white semi-solid. Purification of the crude material by flash chromatography gave l-bromo-4- (2-methylsulfonyl) -ethylbenzene (0.283 g, 80%). _{^{1 H-NMR (DMSO- d 6}} , 300 MHz) δ 7.49 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 3.43 (m, 2H), 2.99 (m, 2H ), 2.97 (s, 3H).

Step d: Preparation of 4,4,5,5-tetramethyl-2- (4- (2- (methylsulfonyl) ethyl) -phenyl) -1,3,2-dioxaborolane

Methyl-4- [4- (2-methylsulfonyl) ethyl] phenyl) -1,3,2-dioxaborolane was reacted with 4,4,5,5-tetramethyl- 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] sulfonyl-piperazine (Preparation AA).

CC. Tributylmethyl (4- (4,4,5,5- tetramethyl- 1,3,2 -dioxaborolan -2-yl) benzyl) carbamate

Step a: 3-tert-butyl-4-bromo carbamate

Commercially available p -bromobenzylamine hydrochloride (1 g, 4 mmol) was treated with 10% aqueous NaOH (5 mL). To the clear solution was added (Boc) ₂ O (1.1 g, 4.9 mmol) dissolved in dioxane (10 mL). The mixture was vigorously stirred at room temperature for 18 hours. The obtained residue was concentrated, and suspended in water (20㎖), ethyl acetate (4 × 20㎖) extract, tertiary and dried Na ₂ SO _4, filtered, and concentrated to a white solid by-butyl-4 Bromobenzyl carbamate (1.23 g, 96%). ^{1 H NMR (300 MHz, DMSO-} d 6) δ 7.48 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 6 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 4.07 (d, J = 6.3 Hz, 2H), 1.38 (s, 9H).

Step b: 3-tert-butyl-4-bromobenzyl (methyl) carbamate

In 60㎖ vial was dissolved tert-butyl-4-bromo-benzyl carbamate (1.25g, 4.37mmol) in DMF (12㎖). Ag ₂ O (4.0 g, 17 mmol) was added to the solution, followed by CH ₃ I (0.68 mL, 11 mmol). The mixture was stirred at 50 &lt; 0 &gt; C for 18 hours. The reaction mixture was filtered through celite, and the celite was washed with methanol (2 x 20 mL) and dichloromethane (2 x 20 mL). The filtrate was concentrated to remove most of the DMF. The residue is treated with water (50 mL) and a white emulsion is formed. The mixture extracted with ethyl acetate (4 × 25㎖) and, Na ₂ SO ₄ dried, the solvent was evaporated tert -butyl-4-bromobenzyl (methyl) carbamate a yellow (1.3g, 98%) As an oil. ^{1 H NMR (300 MHz, DMSO-} d 6) δ 7.53 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.32 (s, 2H), 2.74 (s, 3H) , 1.38 (s, 9 H).

Step c: tert- Butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzylmethylcarbamate

Phenyl) sulfonyl-piperazine (Preparation AA) was reacted with 1-methyl-4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- Coupling reaction was achieved in the same manner as described. After the coupling reaction, the crude reaction mixture was treated with 0.5 mL of 1N HCl in diethyl ether for 18 hours to remove the Boc protecting group and then purified by HPLC.

A further example of the present invention was prepared according to the above process without substantial change, except that the arylboronic acid shown in Table 4 was used.

(a) The crude reaction mixture was treated with 0.5 mL of 1N HCl in diethyl ether for 18 hours to remove the Boc protecting group after the coupling reaction and then purified by HPLC.

Further embodiments of the invention may be prepared by modifying the intermediates described above.

Compound after coupling Derivatization :

DD. 1- (benzo [d] [1,3] dioxol-5-yl) -N- (6- (4- (2- methyl-pyrrolidin-1-sulfonyl some accounts) Fe carbonyl) pyridin-2-yl) Cyclopropanecarboxamide

Step a: 4- (4,4'-Dimethoxybenzhydryl) -thiophenylboronic acid

4,4'-Dimethoxybenzhydrol (2.7 g, 11 mmol) and 4-mercaptophenylboronic acid (1.54 g, 10 mmol) were dissolved in 20 mL of AcOH and heated at 60 ° C for 1 hour. The solvent was evaporated and the residue was dried under high vacuum. The material was used without further purification.

Step b: Preparation of 6- (4- (bis (4-methoxyphenyl) methylthio) phenyl) pyridin-

(10 mmol) and 2-amino-6-bromopyridine (1.73 g, 10 mmol) were dissolved in MeCN (40 ml) and then Pd (PPh ₃₎ was added ₄ (~ 50㎎) and aqueous _{K 2 CO 3 (1M, 22㎖} ). The reaction mixture was divided and heated in a microwave oven (160 &lt; 0 &gt; C, 400 sec). The product was partitioned between ethyl acetate and water. The organic layers were washed with water, brine, dried over MgSO _4. The volatiles were evaporated to give an oil which was used in the next step without further purification. ESI-MS m / z calc 428.0, found 429.1 (M + 1).

Step c: 1- (benzo [d] [1,3] dioxol-5-yl) - N - (6- (4- (bis (4-methoxyphenyl) methyl) phenyl) -pyridin-2 Yl) cyclopropanecarboxamide

(~ 10 mmol) of 6 - [(4,4'-dimethoxybenzhydryl) -4-thiophenyl] pyridin-2-ylamine and 1-benzo [1,3] dioxol-5-yl-cyclopropanecarboxylic acid (2.28 g, 11 mmol) was dissolved in chloroform (25 mL), then TCPH (4.1 g, 12 mmol) and DIEA (5 mL, 30 mmol) were added. The reaction mixture was heated at 65 &lt; 0 &gt; C for 48 hours and then the volatiles were removed under reduced pressure. The residue was transferred to a separatory funnel and partitioned between water (200 mL) and ethyl acetate (150 mL). The organic layer was washed with 5% NaHCO ₃ (2 x 150 mL), water (1 x 150 mL), brine (1 x 150 mL) and dried over MgSO ₄ . Evaporation of the solvent crude l- (benzo [d] [1,3] dioxol-5-yl) - N - (6- (4- (bis (4-methoxyphenyl) methyl) phenyl) pyridin- 2-yl) cyclopropanecarboxamide as a light oil. ESI-MS m / z calc 616.0, found 617.0 (M + 1) (HPLC purity ~ 85%, UV 254 nm).

Step d: Preparation of 4- (6- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) pyridin-

Yl) - N - (6- (4- (bis (4-methoxyphenyl) methylthio) -phenyl) pyridin- propane car carboxamide (~ 8.5mmol) was added which _{then, 30% H 2 O 2 (} 10㎖) dissolved in AcOH (75㎖). Additional hydrogen peroxide (10 ml) was added after 2 hours. The reaction mixture was stirred at 35-45 [deg.] C overnight (~ 90% conversion, HPLC). The volume of the reaction mixture was reduced by one-third by evaporation (bath temperature less than 40 ° C). The reaction mixture was directly weighted and purified by preparative HPLC column (C-18). The fractions with 4- (6- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropanecarboxamido) pyridin-2- yl) benzenesulfonic acid were collected and evaporated (1.9 g, 43%, calculated on the basis of 4-mercapto-phenylboronic acid). ESI-MS m / z calc 438.0, found 438.9 (M + 1).

Step e: Preparation of 4- (6- (1- (benzo [d] [1,3] dioxol-5-yl) cyclopropane-carboxamido) pyridin-

Yl) benzenesulfonic acid (1.9 g, 4.3 mmol) was added to a solution of POCl (2, 3, ₃ (30 mL), SOCl ₂ (3 mL) and DMF (100 μL) were added. The reaction mixture was heated at 70-80 &lt; 0 &gt; C for 15 min. The volatiles were evaporated and then re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and used immediately for sulfonylation. ESI-MS m / z calc 456.0, found 457.1 (M + 1).

Step f: 1- (benzo [d] [1,3] dioxol-5-yl) - N - (6- (4- (2- methyl-pyrrolidin-1-some accounts) phenyl) pyridin-2- Yl) cyclopropanecarboxamide

2-yl) benzene-1-sulfonyl chloride (~35 μmol, chloroform (1 mmol) in dichloromethane Was treated with 2-methylpyrrolidine and then DIEA (100 μl) was added. The reaction mixture was held at room temperature for 1 hour, concentrated and then diluted with DMSO (400 [mu] l). The resulting solution was treated with HPLC purification. The fractions containing the desired material were combined and concentrated in a vacuum centrifuge at 40 ° C to give the trifluoroacetic acid salt of the target material (ESI-MS m / z calcd 505.0, found 505.9 (M + 1) 4.06 min). ^{1 H NMR (250 MHz, DMSO-} d 6) δ 1.15 (m. 2H), δ 1.22 (d, 3H, J = 6.3 Hz), δ 1.41-1.47 (m, 2H), δ 1.51 (m, 2H) , 6.03 (s, 2H), [delta] 6.96-7.06 (m, 2H), [delta] 1.52-1.59 2H), 7.71 (d, 1H, J = 1.3 Hz), 7.78 (d, 1H, J = 8.2 Hz) = 8.2 Hz), 8 8.08 (d, 1H, J = 8.2 Hz), 8 8.16 (d, 2H, J = 8.5 Hz),? 8.53 (s, 1H).

The compounds in the following table were synthesized as described above using commercially available amines. A further example of the present invention was prepared according to the above process without substantially changing it except for using the amines shown in Table 5.

EE. 1-benzo [1,3] dioxol-5-yl-N - [6- [4 - [(methyl-methylsulfonyl-amino) methyl] Fe carbonyl] -2-pyridyl] - cyclopropane-1- Carboxamide (Compound No. 292)

Dichloroethane (DCE) (1.5 mL) was added to the starting amine (brown solid, 0.100 g, ~ 0.2 mmol, treated with 1N HCl in ether to yield the corresponding t -butyloxycarbonyl derivative) followed by pyridine (0.063 ml, 0.78 mmol) and methanesulfonyl chloride (0.03 ml, 0.4 mmol) were added. The mixture was stirred at 65 &lt; 0 &gt; C for 3 hours. LC / MS analysis then showed 50% conversion to the desired product. Two additional equivalents of pyridine and 1.5 equivalents of methanesulfonyl chloride were added and the reaction was stirred for 2 hours. The residue was concentrated and purified by HPLC to give 1-benzo [1,3] dioxol-5-yl- N- [6- [4- [methyl- methylsulfonyl- amino) methyl] phenyl] Yl] -cyclopropane-1-carboxamide (0.020 g, yield 21%) as a white solid. ESI-MS m / z calc 479.2, found 480.1 (M + l) ⁺ .

FF. (R) -1- (3- hydroxy-4-methoxyphenyl) - N - (6- (4- (2- ( hydroxymethyl) - pyrrole-1-naphthyridin some accounts) phenyl) pyridin-2- Yl) cyclopropanecarboxamide

(R) -1- (3- (benzyloxy) -4-methoxyphenyl) - N - (6- (4- (2- ( hydroxymethyl) pyrrolidin-1-some accounts) phenyl) pyridin- 2-yl) cyclopropanecarboxamide (28 mg, 0.046 mmol) was dissolved in ethanol (3 mL). Palladium on charcoal (10%, 20 mg) was added and the reaction was stirred under 1 atm of hydrogen overnight. The catalyst was filtered off, the product was separated by silica gel chromatography (50-80% EtOAc in hexane) to (R) -1- (3- hydroxy-4-methoxyphenyl) - N - (6- (4- (2- (hydroxymethyl) pyrrolidin-1-ylsulfonyl) phenyl) pyridin-2-yl) cyclopropanecarboxamide (8 mg, 34%). ESI-MS m / z calcd 523.4, found 524.3 (M + l) ⁺ . Retention time 3.17 minutes.

2-Amino-5-phenylpyridine (CAS [33421-40-8]) is C-1.

GG. (R) - (1- (4- (6- amino-pyridin-2-yl) phenylsulfonyl) pyrrolidin-2-yl) methanol and Jethro chloride (C-2)

Step a: ( R ) - (1- (4-Bromophenylsulfonyl) pyrrolidin-2-yl)

4-bromo in methanol mixture in CH ₂ Cl ₂ (100㎖) of (53g, 0.53mol) - saturated aqueous _{NaHCO 3 (44g, 0.53mol),} CH 2 Cl 2 (400㎖) and pyrrolidin-2-yl A solution of mo-benzenesulfonyl chloride (127 g, 0.50 mol) was added. The reaction was stirred overnight at 20 &lt; 0 &gt; C. The organic phase was separated, dried over Na ₂ SO _4. The solvent was evaporated under reduced pressure to give ( R ) - (1- (4-bromophenylsulfonyl) pyrrolidin-2-yl) methanol (145 g, crude product) Respectively. ¹ H NMR (CDCl _{3 ,} 300 MHz)? 7.66-7.73 (m, 4 H), 3.59-3.71 (m, 3 H), 3.43-3.51 , 1.680-1.88 (m, 3H), 1.45-1.53 (m, 1H).

Step b: ( R ) -l- (4-Bromo-benzenesulfonyl) -2- ( tert -butyl-dimethyl-silanyloxymethyl) pyrrolidine

(50.0 g, 0.16 mol) and 1 H-imidazole (21.3 g, 0.31 mol) in CH ₂ Cl ₂ (500 mL) to a solution of mol) was added into the tert-butyl-chloro-dimethyl-silane (35.5g, 0.24mol). After the addition, the mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (200 mL) and the separated aqueous layer was extracted with CH ₂ Cl ₂ (100 mL × 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and evaporated in vacuo to give 1- (4-bromo-benzenesulfonyl) -2- ( tert- butyldimethylsilanyloxymethyl) pyrrolidine 68.0 g, 99%). ¹ H NMR (300 MHz, CDCl ₃ )? 7.63-7.71 (m, 4H), 3.77-3.81 (m, 1H), 3.51-3.63 , 3.02-3.07 (m, 1 H) , 1.77-1.91 (m, 2 H), 1.49-1.57 (m, 2 H), 0.87 (s, 9 H), 0.06 (d, J = 1.8 Hz, 6 H ).

Step c: (R) -4- (2 - ((3 -tert-butyldimethylsilyloxy) methyl) pyrrolidin-1-some accounts) phenyl boronic acid

To a solution of 1- (4-bromo-benzenesulfonyl) -2- ( tert -butyl-dimethyl-silanyloxymethyl) pyrrolidine (12.9 g, 29.7 mmol) and B (O ⁱ Pr ) ₃ (8.4g, 45mmol) at -70 &lt; 0 &gt; C was added dropwise n- BuLi (2.5M in hexanes, 29.7ml). After the addition, the mixture was slowly warmed to -10 C and treated with HCl (1 M, 50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with Na ₂ SO ₄ and evaporated in vacuo. The combined organics were crude (R) -4- (2 - ( (3 -tert-butyldimethylsilyloxy) methyl) pyrrolidin-1-sulfonyl some accounts) to give the boronic acid (15.0g), and used directly in the next step Respectively.

Step d: (6- {4- [2- ( tert- Butyl-dimethyl-silanyloxymethyl) -pyrrolidine- 1 -sulfonyl] phenyl} pyridin- 2- yl) carbamic acid tert- butyl ester

DMF (250㎖) of (6-bromo-pyridin-2-yl) carbamic acid tert-butyl ester To a solution of (24.6g, 90.0mmol), (R) -4- (2 - ((tert-butyldimethylsilyl oxy) methyl) pyrrolidin-1-some accounts) phenyl boronic acid _{(45.0g), Pd (PPh 3} ) 4 (10.4g, 9.0mmol), potassium carbonate (18.6g, 135mol) and water (200㎖) Were added. The resulting mixture was degassed by bubbling argon gently through the solution at 20 &lt; 0 &gt; C for 5 minutes. The reaction mixture was then heated at 80 &lt; 0 &gt; C overnight. DMF was removed under vacuum. To the residue was added EtOAc (300 mL). The mixture was filtered through a pad of silica gel, which was washed with EtOAc (50 mL x 3). The combined organic extracts were evaporated in vacuo. The crude residue was purified by column (petroleum ether / EtOAc 20: 1) to give (6- {4- [2- ( tert- butyl- dimethyl- silanyloxymethyl) pyrrolidine- 1 -sulfonyl] phenyl} 2-yl) carbamic acid tert- butyl ester (22.2 g, 45% over both steps). ^{1 H NMR (300 MHz, CDCl} 3) δ 8.09 (d, J = 8.4 Hz, 2 H), 7.88-7.96 (m, 3 H), 8.09 (t, J = 7.8 Hz, 1 H), 7.43-7.46 (m, 1H), 7.38 (s, 1H), 3.83-3.88 (m, 1H), 3.64-3.67 , 1 H), 3.08-3.16 (m, 1H), 1.82-1.91 (m, 2H), 1.67-1.69 H), 0.08 (d, J = 2.4 Hz, 6 H).

Step e: {6- [4- (2-Hydroxymethyl-pyrrolidine-1-sulfonyl) -phenyl] pyridin- 2- ylcarbamic acid tert- butyl ester

The title compound was prepared from crude (6- {4- [2- ( tert- butyl-dimethyl-silanyloxymethyl) -pyrrolidine- 1 -sulfonyl] phenyl} -pyridin-2- yl) carbamic acid 3 A solution of tert- butyl ester (22.2 g, 40.5 mmol) and TBAF (21.2 g, 81.0 mmol) was stirred at room temperature overnight. The mixture was washed with brine (100 mL x 3), dried over Na ₂ SO ₄ and evaporated in vacuo to give {6- [4- (2-hydroxymethyl-pyrrolidine- 1 -sulfonyl) Pyridin-2-yl} carbamic acid tert- butyl ester (15.0 g, 86%) which was used directly in the next step.

Step f: ( R ) - (1- (4- (6-aminopyridin-2-yl) phenylsulfonyl) -pyrrolidin- 2- yl) methanol hydrochloride

-Phenyl] pyridin-2-yl} carbamic acid tert- butyl ester (15.0 g, 15 mmol) in HCl / MeOH (50 mL, , 34.6 mmol) was heated at reflux for 2 hours. After cooling to room temperature the reaction mixture was evaporated in vacuo and washed with EtOAc to give ( R ) - (1- (4- (6-aminopyridin-2-yl) phenylsulfonyl) pyrrolidin- Methanol hydrochloride (C-2; 11.0 g, 86%) was obtained. ^{1 H NMR (300 MHz, DMSO-} d 6) δ 8.18 (d, J = 8.7 Hz, 2 H), 7.93-7.99 (m, 3 H), 7.31 (d, J = 7.2 Hz, 1 H), 7.03 (d, J = 8.7 Hz, 1 H), 3.53-3.57 (m, 2 H), 3.29-35 (m, 2 H), 3.05-3.13 (m, 1 H), 1.77-1.78 (m, 2 H ), 1.40-1.45 (m, 2H). MS (ESI) m / z (M + H) &lt; ⁺ & gt ^; 334.2.

HH. N - (4- (6 -aminopyridin - 2 -yl) benzyl) methanesulfonamide (C-3)

Step a: [6- (4-Cyano-phenyl) -pyridin-2-yl] carbamic acid tert- butyl ester

4-cyano-benzene boronic acid (7.35g, 50mmol), (6- bromo-2-yl) in: (1, 250㎖ 1) carbamic acid tert-butyl ester (13.8g, DMF / H ₂ O A mixture of Pd (Ph ₃ P) ₄ (5.8 g, 0.15 mmol) and K ₂ CO ₃ (10.4 g, 75 mmol) was stirred at 80 ° C. overnight under argon. DMF was evaporated under reduced pressure and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried with Na ₂ SO _4, and concentrated to dryness. The residue was purified by silica gel column (petroleum ether / EtOAc 50: 1) to give [6- (4-cyano-phenyl) -pyridin-2- yl] carbamic acid tert- butyl ester (7.0 g, 60% Respectively. ¹ H NMR (300 MHz, CDCl ₃ )? 8.02-8.07 (m, 2H), 7.95 (d, J = 8.4 Hz , 1H), 7.71-7.79 (m, 3H), 7.37-7.44 2 H), 1.53 (s, 9 H).

Step b: [6- (4-Aminomethyl-phenyl) -pyridin-2-yl] -carbamic acid tert- butyl ester

Pyridin-2-yl] carbamic acid tert- butyl ester (7.0 g, 24 mmol) in EtOH (500 mL) and NH ₃ .H ₂ O (10 mL), Raney Ni (1.0 g) was hydrogenated at 50 &lt; 0 &gt; C for 6 h under H ₂ (50 psi.). The catalyst was filtered off and the filtrate was concentrated to dryness to give [6- (4-aminomethyl-phenyl) -pyridin-2-yl] -carbamic acid tert- butyl ester, which was used directly in the next step. ¹ H NMR (300 MHz, CDCl ₃ )? 7.83-7.92 (m, 3H), 7.70 (t, J = 7.8 Hz , 1H), 7.33-7.40 , 1.53 (s, 9 H).

Step c: {6- [4- (Methanesulfonylamino-methyl) -phenyl] -pyridin-2-yl} carbamic acid tert- butyl ester

To a solution of carbamic acid tert-butyl ester (5.7g 19mmol) and _{Et 3 N (2.88g, 29mmol)} - dichloromethane (50㎖) of [6- (4-amino-phenyl) -pyridin-2-yl; MsCl (2.7 g, 19 mmol) was added dropwise at 0 &lt; 0 &gt; C. The reaction mixture was stirred at this temperature for 30 minutes, washed with water and brine, dried over Na ₂ SO _4, and concentrated to dryness. The residue was recrystallized from DCM / petroleum ether (1: 3) to give {6- [4- (methanesulfonylamino-methyl) -phenyl] -pyridin-2- yl} carbamic acid tert- butyl ester Step 44%). &Lt; / RTI &gt; ¹ H NMR (300 MHz, CDCl ₃ )? 7.90-7.97 (m, 3 H), 7.75 (t, J = 8.4, 8.4 Hz, 1H), 7.54-7.59 (m, 1H), 7.38-7.44 m, 3 H), 4.73 (br, 1H), 4.37 (d, J = 6.0 Hz, 2H), 2.90 (s, 3H), 1.54 (s, 9H).

Step d: Preparation of N- (4- (6-aminopyridin-2-yl) benzyl) methane- sulfonamide (C-

A mixture of {6- [4- (methanesulfonylamino-methyl) -phenyl] -pyridin-2-yl} carbamic acid tert- butyl ester (11 g, 29 mmol) in HCl / MeOH (4M, And stirred overnight. The mixture was concentrated to dryness. The residue was filtered and washed with ether to give N - (4- (6-aminopyridin-2-yl) benzyl) methanesulfonamide (C-3) (7.6 g, 80%). ^{1 H NMR (300 MHz, DMSO} -d 6) δ 14.05 (br s, 1 H), 8.24 (br s, 2 H), 7.91-7.98 (m, 3 H), 7.70 (t, J = 6.0 Hz, (D, J = 6.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.22 Hz, 2 H), 2.89 (s, 3 H). MS (ESI) m / z (M + H) &lt; ⁺ & gt ^; : 278.0,

II. 4- (6 -aminopyridin - 2 -yl) -N - methylbenzenesulfonamide Hydrochloride (C- 4)

Step a: 4-Bromo- N -methyl-benzenesulfonamide

Saturated aqueous _{NaHCO 3 (42g, 0.5mol),} CH 2 Cl 2 (400㎖) and methylamine To a mixture of (51.7g, 0.5mol, 30% in methanol) CH ₂ Cl ₂ (100㎖) solution of 4-bromo -Benzenesulfonyl chloride (127 g, 0.5 mol) in dichloromethane was added. The reaction was stirred overnight at 20 &lt; 0 &gt; C. The organic phase was separated, dried over Na ₂ SO _4. Evaporation of the solvent under reduced pressure gave 4-bromo- N -methyl-benzenesulfonamide (121 g, crude product) which was used in the next step without further purification. ¹ H NMR (CDCl _{3 ,} 300 MHz)? 7.64-7.74 (m, 4 H), 4.62-4.78 (m, 1H), 2.65 (d, J = 5.4 Hz, 3 H).

Step b: Preparation of 4- ( N -methylsulfamoyl) phenylboronic acid

To a solution of 4-bromo- N -methyl-benzenesulfonamide (24.9 g, 0.1 mol) and B (O ⁱ Pr) ₃ (28.2 g, 0.15 mol) in THF (200 mL) (100 mL, 0.25 mol) was added. The mixture was slowly warmed to 0 &lt; 0 &gt; C and then 10% HCl solution was added to pH 3-4. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and evaporated under reduced pressure to give 4- ( N -methylsulfamoyl) phenylboronic acid (22.5 g, 96%) which was used in the next step without further purification. _{^{1 H NMR (DMSO- d 6,}} 300 MHz) δ 8.29 (s, 2 H), 7.92 (d, J = 8.1 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2 H), 2.36 (d , &Lt; / RTI &gt; J = 5.1 Hz, 3 H).

Step c: tert- Butyl 6- (4- ( N -methylsulfamoyl) phenyl) pyridin-2-ylcarbamate

To a solution of 4- ( N -methylsulfamoyl) phenylboronic acid (17.2 g, 0.08 mol) and (6-bromo-pyridin-2- yl) carbamic acid tert -butyl ester in DMF (125 mL) and H ₂ O to a solution of butyl ester (21.9g, 0.08mol) was added _{Pd (PPh 3) 4 (9.2g} , 0.008mol) and _{K 2 CO 3 (16.6g, 0.12mol} ). The resulting mixture was degassed by bubbling argon gently through the solution at 20 &lt; 0 &gt; C for 5 minutes. The reaction mixture was then heated at 80 &lt; 0 &gt; C for 16 hours. The mixture was evaporated under reduced pressure, then poured into H ₂ O and extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and evaporated under reduced pressure to give tert- butyl 6- (4- ( N -methylsulfamoyl) phenyl) pyridin-2-ylcarbamate (21 g, 58% It was used in the next step without further purification.

Step d: 4- (6-Aminopyridin-2-yl) -N -methylbenzenesulfonamide hydrochloride

To a solution of tert- butyl 6- (4- ( N -methylsulfamoyl) phenyl) pyridin-2-ylcarbamate (8.5 g, 23.4 mmol) in MeOH (10 mL) at room temperature was added HCl / MeOH ) Was added. The suspension was stirred overnight at room temperature. The solid product was collected by filtration, washed with MeOH and dried to give 4- (6-aminopyridin-2-yl) -N -methylbenzenesulfonamide hydrochloride (5.0 g, 71%). ¹ H NMR (300 Hz, DMSO- d ₆ )? 8.12 (d, J = 8.4 Hz, 2H), 7.91-7.96 (m, 3H), 7.58-7.66 (m, 1H), 7.31-7.53 m, 1H), 7.27 (d, J = 6.6,1H), 6.97 (d, J = 9.0,1H), 2.43 (d, J = 4.8 Hz, 3H). MS (ESI) m / z (M + H) &lt; ⁺ & gt ^; 264.0.

The compounds in the following table were synthesized as described above, either commercially or using the carboxylic acids and amines described above.

The physical data for an embodiment of the present invention is presented in Table 7.

Additional exemplary compounds 164-388 shown in Table 1 can also be prepared using the appropriate starting materials and methods illustrated for the compounds described above.

black

The &lt; RTI ID = 0.0 & CFTR  Test for detection and measurement of correction characteristics

JJ. Optical membrane potential method for testing the ΔF508- CFTR adjust properties of the compounds

Optical film potential assays are performed using a fluorescence change measurement instrument such as a voltage / iron probe reader (VIPR) (Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4 (9): 431-439, Gonzalez, JE and RY Tsien Chem. Biol. 4 (4): 269-7. " Energy transfer in single cells "Biophys J 69 (4): 1272-80 and Gonzalez, JE and RY Tsien The voltage sensitive FRET sensor described in [77] was used.

This voltage sensitive assay is based on changes in fluorescence resonance energy transfer (FRET) between the membrane-soluble, voltage sensitive dye DiSBAC ₂ (3) and the fluorescent phospholipid CC2-DMPE (attached to the outer leaflet of the plasma membrane and acting as an FTET donor) . The change in membrane potential (V _m ) redistributes the negatively charged DiSBAC ₂ (3) across the plasma membrane and changes the amount of energy transfer from CC2-DMPE. Changes in fluorescence emission were monitored using an integrated liquid handler and a fluorescence detector, VIPR ^TM II, designed to perform cell-based screens on 96-well or 384-well microtiter plates.

1. Identification of calibration compounds

To identify small molecules that correct for traffic-king defects associated with ΔF508-CFTR, a single-add HTS assay format was developed. Cells were cultured in serum-free medium for 16 hours at 37 ° C under the presence or absence of the test compound (negative control). As a positive control, cells stained in 384-well plates were incubated for 16 hours at &lt; RTI ID = 0.0 &gt; 27 C &lt; / RTI &gt; Cells were then washed three times with solutions (Krebs Ringers) and loaded with voltage sensitive dye. To activate ΔF508-CFTR, 10 μM forskolin and the CFTR Cl Potency initiator (potentiator), genistein (20 μM) to each well ^were taken together with the non-containing medium. ^{Cl-containing} medium is a non-addition of ΔF508-CFTR in response to activation ^Cl-enhanced fine outlet, the membrane a voltage based on the depolarization FRET- generating - with the sensor dye was monitored optically.

2. Potentiator  Identification of compounds

To identify the potentiator of ΔF508-CFTR, a double-additive HTS assay format was developed. Cl claim 1 in the presence or absence of a test compound was added ^for-the-free medium was added to each well. After 22 seconds, Cl containing 2 to 10 μM ^forskolin-by adding a second additive-free medium was activate ΔF508-CFTR. The added extracellular Cl ^- concentration after addition was 28 mM, which enhanced Cl ^- efflux in response to ΔF508-CFTR activation, and the resulting membrane depolarization was monitored optically using a FRET-based voltage-sensor dye Respectively.

3. Solution

Blood # 1: (mM) NaCl 160, KCl 4.5, CaCl ₂ 2, MgCl ₂ 1, HEPES 10, pH 7.4 (using NaOH).

Chloride-free bath solution: the chloride salt in bath # 1 was replaced with gluconate salt.

CC2-DMPE: prepared as a 10 mM stock solution in DMSO and stored at -20 ° C.

DiSBAC ₂ (3): prepared as 10 mM stock in DMSO and stored at -20 ° C.

4. Cell culture

NIH3T3 mouse fibroblasts stably expressing? F508-CFTR were used for optical measurement of membrane potentials. Cells were grown in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 x NEAA, beta-ME, 1 x pen / strep and 25 mM HEPES in a 175 cm 2 culture flask with 5% CO ₂ and 90% humidity at &lt; RTI ID = 0.0 &gt; 37 C. &lt; / RTI &gt; For all optical assays, cells were seeded at 30,000 / well in 384-well matrigel-coated plates, incubated at 37 [deg.] C for 2 hours and then incubated at 27 [deg.] C for 24 hours for potentiator assays. For calibration assays, cells were incubated for 16-24 hours at 27 ° C or 37 ° C in the presence or absence of compound.

The &lt; RTI ID = 0.0 & CPTR  Electrophysiological assay for assaying regulatory properties

One. Yushing ( Ussing ) chamber  black

Confirmed chamber experiments in optical assays performed excitation chamber experiments on polarized epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulator. FRT [ ^{Delta] F508- CFTR} epithelial cells grown in Costar Snapwell cell culture inserts were ^placed in a dissecting chamber (Physiologic Instruments, Inc., San Diego, Calif.) And placed in a Voltage-clamp System , University of Iowa, IA, and Physiologic Instruments, Inc., San Diego, Calif.). The transdermal resistance was measured by applying a 2-mV pulse. Under these conditions, the FRT epithelium exhibited a resistance of at least 4 K? / CM ² . The solution was maintained at 27 占 폚 and bubbled with air. The electrode offset potential and fluid resistance were corrected using a cell-free insert. Under these conditions, the current reflects the flow of Cl ^- through the ΔF508-CFTR expressed in the tip membrane. I _sc was digitized using the MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, Calif.).

2. Identification of Calibration Compounds

The basal side was used for the affixed Cl ^- concentration gradient according to the usual protocol. To establish this gradient, a large Cl ^- concentration gradient was made across the epithelium using a normal ringer on the basolateral membrane and replacing the apex NaCl with an equimolar amount of sodium gluconate (titrated to pH 7.4 with NaOH). All experiments were performed with intact monolayer. To fully activate ΔF508-CFTR, forskolin (10 μM) and PDE inhibitor IBMX (100 μM) were added and CFTR potentiator, genistein (50 μM) was added.

As observed in other cell types, culturing FRT cells stably expressing [Delta] F508-CFTR at low temperature increases the functional density of CFTR in the plasma membrane. To determine the activity of the correcting compounds, the cells were incubated with 10 [mu] M test compound for 24 hours at 37 [deg.] C and washed three times before recording. CAMP- and genistein-mediated I _sc in compound treated cells was normalized for 27 &lt; 0 &gt; C and 37 &lt; 0 &gt; C controls and expressed as% activity. Preincubation of the cells with the calibrator compound resulted in a significant increase in cAMP- and zenith-mediated I _sc as compared to the control at 37 ° C.

3. Potentiator  Identification of compounds

The basal side was used for the affixed Cl ^- concentration gradient according to the usual protocol. To establish this gradient, a normal linger was used for the basolateral membrane, permeabilized with nystatin (360 ug / ml), and peak NaCl replaced with an equimolar amount of sodium gluconate (titrated with NaOH at pH 7.4) To create a large Cl ^- concentration gradient across the epithelium. All experiments were performed 30 minutes after nystatin permeation treatment. Forskolin (10 μM) and all test compounds were added to both sides of the cell culture insert. The potency of the estimated [Delta] F508-CFTR potentiator was compared to that of the known potentiator, genistein.

4. Solution

The base-side solution (mM): NaCl (135) , CaCl 2 (1.2), MgCl 2 (1.2), K 2 HPO 4 (2.4), KHPO 4 (0.6), N-2- hydroxyethyl piperazine -N ' -2-ethanesulfonic acid (HEPES) (10), and dextrose (10). The solution was titrated with NaOH to pH 7.4.

Peak Solution (mM): Same as base solution except that NaCl was replaced with Na gluconate (135).

5. Cell culture

^ΔF508-CFTR (FRT ^ΔF509- CFTR) were used for expressing FRT (Fisher rat epithelial) cells in yussing chamber tests for the estimated ΔF508-CFTR adjuster confirmed from the optical black. Cells were cultured on a Costa Snapwell cell culture insert and cultured in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U / ml penicillin and 100 μg / ml streptomycin at 37 ° C. And 5% CO ₂ for 5 days. Prior to use to characterize the potentiator activity of the compounds, the cells were cultured at 27 [deg.] C for 16-48 hours to calibrate [Delta] F508-CFTR. To determine the activity of the calibrating compound, the cells were incubated for 24 hours at 27 [deg.] C or 37 [deg.] C in the presence or absence of compound.

6. Whole cell record

The macroscopic ΔF508-CFTR current ( _IΔF508 ) in the temperature-and test compound-calibrated NIH3T3 cells stably expressing ΔF508-CFTR was monitored using a pore-patch, whole cell record. Briefly, voltage-clamp _recording of I? _F508 was performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, Calif.). All recordings were obtained at a sampling frequency of 10 kHz and a low-pass filtered at 1 kHz. The pipette showed a resistance of 5-6 MΩ when filled with intracellular solution. Under these recording conditions, the reversed potential calculated for Cl ^- (E _cl ) at room temperature was -28 mV. All records had a seal resistance of more than 20 GΩ and a series resistance of less than 15 MΩ. Pulse generation, data accumulation and analysis were performed using a PC equipped with a Digidata 1320 A / D interface with Clampex 8 (Axon Instruments Inc.). The bath contained less than 250 μl of saline and was continuously perfused at a rate of 2 ml / min using a gravity-driven perfusion system.

7. Identification of Calibration Compounds

In order to measure the activity of the correcting compound to increase the density of functional ΔF508-CFTR in the plasma membrane, we measured the current density after 24 hours treatment with a correction compound using the perforated patch recording technique described above. To fully activate [Delta] F508-CFTR, 10 [mu] M forskolin and 20 [mu] M genistein were added to the cells. Under the recording conditions of our inventor, the current density after incubation at 27 ° C for 24 hours was higher than the observed current density after incubation at 37 ° C for 24 hours. These results are consistent with the known effect of low temperature incubation on the density of ΔF508-CFTR in plasma membranes. To determine the effect of calibration compound on CFTR current density, cells were incubated with 10 [mu] M test compound for 24 hours at 37 [deg.] C and the current density was compared to 27 [deg.] C and 37 [deg.] C control (% activity). Prior to recording, the cells were washed three times with the extracellular recording medium to remove the remaining test compound. The preincubation with the 10 μM calibration compound resulted in a significant increase in cAMP- and senescence-dependent currents at 37 ° C compared to the control.

8. Potentiator  Identification of compounds

The ability of the ΔF508-CFTR _potentiator to increase the macroscopic ΔF508-CFTR Cl ^- current ( _IΔF508 ) in NIH3T3 cells stably expressing ΔF508-CFTR was examined using perforation patch recording technology. Potentiators identified from optical assays _showed a dose-dependent increase in I [ _{Delta] F5O8} with similar efficacy and efficiency as observed in optical assays. In all irradiated cells, the reversal potential before and during application of the potentiator was about -30 mV (calculated E _Cl : -28 mV).

9. Solution

Intracellular solution (mM): Cs-aspartate (90), CsCl (50), MgCl ₂ (1), HEPES (10) and 240 μg / ml amphotericin-B (pH 7.35 adjusted with CsOH).

Extracellular solution (mM): N-methyl-D-glucamine (NMDG) -Cl (150), MgCl ₂ (2), CaCl ₂ (2), HEPES (10) (pH 7.35 adjusted with HCl).

10. Cell culture

NIH3T3 mouse fibroblasts stably expressing [Delta] F508-CFTR were used for whole cell recordings. Cells were cultured in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 x NEAA, beta-ME, 1 x pen / strep and 25 mM HEPES in 175 cm 3 culture flasks under 5% CO ₂ and 90% Gt; 37 C. &lt; / RTI &gt; For total cell recording, 2,500 to 5,000 cells were seeded onto poly-L-lysine-coated glass cover slips and incubated at 27 占 폚 for 24-48 hours before testing the activity of the potentiator; And incubated in the presence or absence of the calibration compound to measure the activity of the correcting agent at 37 &lt; 0 &gt; C.

11. Single channel recording

The activity of single-channel activity and potentiator compounds of temperature-compensated ΔF508-CFTR stably expressed in NIH3T3 cells was observed using an inside-out membrane patch. Briefly, single-channel active voltage-clamp recording was performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were obtained at a sampling frequency of 10 kHz and low pass filtered at 400 Hz. The patch pipette was made from Corning Kovar Sealing # 7052 glass (World Precision Instruments, Inc., Sarasota, Fla.) And had a resistance of 5-8 MΩ when filled with extracellular solution. After dissection, 1 mM Mg-ATP, and 75 nM cAMP dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, Wis.) Were activated to activate ΔF508-CFTR. After stabilizing the channel activity, the patch was perfused using a gravity-driven micro-perfusion system. The influent was placed adjacent to the patch and the solution was completely replaced within 1-2 seconds. To maintain ΔF508-CFTR activity during rapid perfusion, the nonspecific phosphatase inhibitor F ^- (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout patch recording (less than 60 minutes). The current generated by a positive charge (anion movement in the opposite direction) moving from the intracellular solution to the extracellular solution is represented by a positive current. The pipette potential (V _p ) was maintained at 80 mV.

Channel activity was analyzed from membrane patches containing no more than two active channels. The maximum number of simultaneous openings during the course of the experiment was determined by the number of active channels. To measure the single-channel current magnitude, the recorded data from the? F508-CFTR activity of 120 seconds was "off-line" filtered at 100 Hz and analyzed using Bio-Patch Analysis software (Bio-Logic Comp. France) point size histogram fitting to a multigausian function. The total microcurrent and Po (open probability) were measured from 120 sec channel activity. Po was determined from Bio-Patch software or from the relationship Po = I / i (N) [I: average current, i: single-channel current magnitude, N: number of active channels in the patch].

12. Solution

Extracellular solution (mM): NMDG (150), aspartate (150), CaCl ₂ (5), MgCl ₂ (2) and HEPES (10) (pH 7.35 adjusted with Tris base).

Intracellular solution (mM): NMDG-Cl (150), MgCl ₂ (2), EGTA (5), TES (10) and Tris base (14) (pH 7.35 adjusted with HCl).

13. Cell culture

NIH3T3 mouse fibroblasts stably expressing [Delta] F508-CFTR were used for incision-patch-clamp recording. Cells were cultured in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 x NEAA, beta-ME, 1 x pen / strep and 25 mM HEPES in a 175 cm 2 culture flask under 5% CO ₂ and 90% Gt; 37 C. &lt; / RTI &gt; For single channel recording, 2,500 to 5,000 cells were seeded in poly-L-lysine-coated cover slip and incubated at 27 占 폚 for 24-48 hours before use.

The exemplified compounds of Table 1 have activity ranging from about 100 nM to 20 [mu] M as determined using the assays described above. The exemplified compounds of Table 1 are found to be sufficiently effective as determined using the assays described above.

Other modes

While the invention has been described in conjunction with the detailed description thereof, it is to be understood that the foregoing description is intended to illustrate and not limit the scope of the invention, which is limited only by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (18)

i) providing a compound of formula (2a) and a compound of formula (2b), and
ii) cross-coupling the compound of formula (2a) and the compound of formula (2b) in a mixture comprising water, a first organic solvent, a first base and a transition metal catalyst to form a compound of formula
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.

Formula 2a

2b
(R ₉ Z ^D ) _1-3 -B (OH) ₂ or a boronic acid ester thereof

(2)

In this formula,
Hal is Cl, Br, or I;
Each R ₈ is independently selected from the group consisting of R ^C , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ Or -OCF _3, and;
Each Z ^C is independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein up to two of the carbon units of Z ^C are optionally and independently replaced by -CO-, CONR ^C -, -CONR ^C NR ^C -, -CO ₂ -, -OCO-, -NR ^C CO ₂ -, -O-, -NR ^C CONR ^C -, -OCONR ^C -, -NR ^C NR ^C - -NR ^C CO-, -S-, -SO-, -SO ₂ -, -NR ^C -, -SO ₂ NR ^C -, -NR ^C SO ₂ - or -NR ^C SO ₂ NR ^C -; R ₈ is ^C 2 -Z to form a ring or a saturated aromatic ring with saturated ring, a partially 4-8 together with the carbon bonded thereto, at which time no more than three ring atoms is O, NH, NR ^C And S;
Each R ^C is independently hydrogen, optionally substituted C _{1 -8} aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heteroalicyclic group (heterocycloaliphatic), optionally substituted aryl or optionally substituted heteroaryl;
Each R ₉ is independently R ^E , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ Or -OCF _3, and;
Each Z ^D is independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein up to two of the carbon units of Z ^D are optionally and independently replaced by -CO-, CONR ^E -, -CONR ^E NR ^E -, -CO ₂ -, -OCO-, -NR ^E CO ₂ -, -O-, -NR ^E CONR ^E -, -OCONR ^E -, -NR ^E NR ^E - -NR ^E CO-, -S-, -SO-, -SO ₂ -, -NR ^E -, -SO ₂ NR ^E -, -NR ^E SO ₂ - or -NR ^E SO ₂ NR ^E -;
Each R ^E is independently hydrogen, optionally substituted C _{1 -8} aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heteroalicyclic group, optionally substituted aryl or optionally substituted heteroaryl;
Ring A is an optionally substituted C _{3 -7} alicyclic or heteroaryl optionally substituted. The method of claim 1, wherein the first organic solvent is an aprotic solvent. The method of claim 1, wherein the first organic solvent is N, N-dimethylformamide. The method of claim 1, wherein the first base is potassium carbonate. The process according to claim 1, wherein the transition metal catalyst is a palladium-based catalyst. The method of claim 5 wherein the palladium-containing catalyst is characterized in that Pd (dppf) Cl _2. The process according to claim 1, wherein the cross-linking reaction is carried out at a temperature of from 80 ° C to 150 ° C. 2. A compound according to claim 1, wherein the compound of formula (2a)
i) reacting a compound of formula (3a) with a compound of formula (3b) in the presence of a first catalyst, and
ii) stirring the mixture comprising the compound of formula 3a, the compound of formula 3b and the first catalyst at an appropriate temperature for an effective period of time
&Lt; / RTI &gt;
Formula 2a

Formula 3a

3b

In this formula,
Hal is Cl, Br, or I;
Each R ₈ is independently selected from the group consisting of R ^C , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ Or -OCF _3, and;
Each Z ^{C is} independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein up to two of the carbon units of Z ^C are optionally and independently replaced by -CO-, -CS-, -CONR ^{C -, -CONR C NR C -} , -CO 2 -, -OCO-, -NR C CO 2 -, -O-, -NR C CONR C -, - OCONR C -, -NR C NR C -, - NR ^C CO-, -S-, -SO-, -SO ₂ -, -NR ^C -, -SO ₂ NR ^C -, -NR ^C SO ₂ - or -NR ^C SO ₂ NR ^C -; Or two R ^C -Z ₈ forms an unsubstituted aromatic ring or a saturated ring, a partially shot 4-8 together with the carbon bonded thereto, wherein the ring atoms of three or less is O, NH, NR ^C , and &lt; RTI ID = 0.0 &gt;S;&lt; / RTI &gt;
Each R ^C is independently hydrogen, optionally substituted C _{1 -8} aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heteroalicyclic group, an optionally substituted aryl or optionally substituted heteroaryl;
Ring A is an optionally substituted C _{3 -7} alicyclic or heteroaryl optionally substituted. 9. The method of claim 8, wherein the effective time is 15 hours. The method of claim 8, wherein the suitable temperature is 110 占 폚. 9. The process of claim 8, wherein the first catalyst is anhydrous pyridine. 9. Compounds of formula I according to claim 8, wherein &lt; RTI ID = 0.0 &gt;
i) reacting a compound of formula (4a) and thionyl chloride in the presence of a second catalyst, and
ii) stirring said mixture comprising a compound of formula (4a), thionyl chloride and a second catalyst at an appropriate temperature for an effective period of time
&Lt; / RTI &gt;
Formula 3a

4a

In this formula,
Each R ₈ is independently selected from the group consisting of R ^C , halo, -OH, -NH ₂ , -NO ₂ , -CN, -CF ₃ Or -OCF _3, and;
Each Z ^{C is} independently a bond or an optionally substituted branched or straight chain C _{1 -6} aliphatic chain wherein up to two of the carbon units of Z ^C are optionally and independently replaced by -CO-, -CS-, -CONR ^{C -, -CONR C NR C -} , -CO 2 -, -OCO-, -NR C CO 2 -, -O-, -NR C CONR C -, - OCONR C -, -NR C NR C -, - NR ^C CO-, -S-, -SO-, -SO ₂ -, -NR ^C -, -SO ₂ NR ^C -, -NR ^C SO ₂ -, or -NR ^C SO ₂ NR ^C -; Or two R ^C -Z ₈ forms an unsubstituted aromatic ring or a saturated ring, a partially shot 4-8 together with the carbon bonded thereto, wherein the ring atoms of three or less is O, NH, NR ^C , and &lt; RTI ID = 0.0 &gt;S;&lt; / RTI &gt;
Each R ^C is independently hydrogen, optionally substituted C _{1 -8} aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heteroalicyclic group, an optionally substituted aryl or optionally substituted heteroaryl;
Ring A is an optionally substituted C _{3 -7} alicyclic or heteroaryl optionally substituted. 13. The method of claim 12, wherein the effective time is 30 minutes. 13. The method of claim 12, wherein the suitable temperature is 60 &lt; 0 &gt; C. 13. The process of claim 12, wherein the second catalyst is N, N-dimethylformamide. 2. A compound according to claim 1, wherein the compound of formula (2a)

(B-12). 2. The compound of claim 1, wherein the compound of formula (2b)

((3- (4,4,5,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid). The compound of claim 1, wherein the compound of formula (2) or a pharmaceutically acceptable salt thereof is

. &Lt; / RTI &gt;